3-aryl-4-hydroxyfuranone compounds and the human and animal health use thereof

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the inhibition of bacterial cell wall biosynthesis and for the therapeutic treatment of bacterial infection or disease in a patient in need thereof. The present invention also provides the use of the formula I compound for the control of ecto- or endoparasites in homeothermic animals.

This application is a divisional of U.S. application Ser. No.10/915,637, filed Aug. 9, 2004, which claims the benefit under 35 U.S.C.§119(e) to U.S. provisional application No. 60/494,330, filed Aug. 11,2003, both of which are hereby incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

In the human pharmaceutical arts, the rapidly developing resistance ofknown bacterial strains to currently prescribed pharmaceuticals hasinitiated a vigorous search for new classes of antibacterial agentshaving alternative modes of action. For example, methicillin resistantS. aureus (MRSA), vancomycin resistant Enterococcus (VRE) and penicillinresistant S. pneumo (PRSP) are bacterial strains which do not respondwell to current clinical drug therapies.

Peptidoglycan is an essential cell wall polymer which forms a sacculusaround the bacterial cell. The biosynthesis of peptidoglycan provides aunique and selective target for antibacterial activity. Peptidoglycanbiosynthesis requires ten specific enzymes to perform as many synthetictransformations. These enzymes include MurA, MurB, MurC, MurD, MurE,MurF, MurG, MraY and the transglycosylase and transpeptidase families ofenzymes. Inhibition of any one of these essential enzymes leads to lossof cell shape and integrity followed by bacterial death. This applies toboth Gram positive and Gram negative microorganisms (Bugg, T. D. et al.,Natural Products Reports 1992 199-215). Of these ten essential enzymes,β-lactam antibiotics inhibit transpeptidases, vancomycin inhibitstransglycosylases and fosfomycin inhibits MurA.

In the animal health arts, virtually all commercial and most companionanimals are affected by ecto- and endoparasites. The outcome associatedwith said parasitic infection or infestation in said animals isgenerally clinical disease and subclinical conditions that decreaseperformance. Insects, such as Phthiraptera (lice) and Diptera (flies),are among the most economically important ectoparasites in animalproduction. Insects, such as Siphonáptera (fleas), are highlypesteriferous to companion animals. Helminths, such as Trichostrongyluscolubriformis, Haemonchus contortus, or the like, are among the mosteconomically important endoparasites in animal production. Nematodes arehighly pesteriferous to companion animals. Ecto- and endoparasiticinfections and infestations not only seriously effect the economies ofraising livestock for meat, wool, hides and milk, but are also a sourceof great concern for companion animals. New, economic alternativemethods and compositions for the prevention, treatment and control ofecto- or endoparasites in warm-blooded animals are constantly beingsought.

Therefore, it is an object of this invention to provide compounds whichinhibit the Mur family of enzymes and are useful as antibacterialagents, particularly against resistant strains of bacteria.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions for the treatment of bacterial infectionor disease.

It is also an object of this invention to provide an effective methodfor the prevention, treatment or control of ecto- or endoparasiticinfection or infestation in homeothermic animals.

It is a further object of this invention to provide an ecto- orendoparasiticidal composition suitable for use on animals and humans.

It is a feature of this invention that the compounds provided herein actas effective inhibitors of bacterial cell wall biosynthesis via the Murenzyme pathway.

Other objects and features of the invention will become more apparent bythe detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

wherein

-   -   R is H;    -   R₁ is phenyl optionally substituted with one, two or three        halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,        C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl group each optionally substituted,        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted,        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted, or        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;    -   R₂ is phenyl optionally substituted with one, two or three        halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,        NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally        substituted with the proviso that only one of R₁ or R₂ may be an        optionally substituted phenyl group;        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each            optionally substituted; or        -   C₃-C₆cycloalkyl optionally substituted with one, two or            three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,            NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,            C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each            optionally substituted;    -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,        C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or        heteroaryl group each optionally substituted;    -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally        substituted C₁-C₆alkyl group; and    -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together        with the atom to which they are attached to form an optionally        substituted 5- to 7-membered ring optionally containing one or        two additional heteroatoms selected from N, O or S; or        a stereoisomer thereof, a tautomer thereof or a pharmaceutically        acceptable salt thereof.

The present invention also provides methods and compositions useful forthe treatment of a bacterial infection or disease in a patient in needthereof.

The present invention further provides a method for the prevention,amelioration or control of ecto- or endoparasitic infection orinfestation in a homeothermic animal which comprises administering tosaid animal a prophylactically, therapeutically or pharmaceuticallyeffective amount of a compound of formula I

wherein

-   -   R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₁ is phenyl optionally substituted with one, two or three        halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,        C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl group each optionally substituted,        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted,        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted, or        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;    -   R₂ is phenyl optionally substituted with one, two or three        halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,        NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally        substituted;        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each            optionally substituted; or        -   C₃-C₆cycloalkyl optionally substituted with one, two or            three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,            NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,            C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each            optionally substituted;    -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,        C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or        heteroaryl group each optionally substituted;    -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally        substituted C₁-C₆alkyl group; and    -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together        with the atom to which they are attached to form an optionally        substituted 5- to 7-membered ring optionally containing one or        two additional heteroatoms selected from N, O or S; or        a stereoisomer thereof, a tautomer thereof or a pharmaceutically        acceptable salt thereof.

The present invention further provides an ecto- or endoparasiticidalcomposition which comprises a pharmaceutically acceptable carrier and anecto- or endoparasiticidally effective amount of a compound of formulaI.

DETAILED DESCRIPTION OF THE INVENTION

Many known antibiotics such as the cephalosporins, the penicillins andvancomycin inhibit the biosynthesis of peptidoglycan, an essential cellwall component of both Gram positive and Gram negative bacteria. Theseantibiotics inhibit membrane-bound enzymes involved in the crosslinkingof the cell wall, i.e., the transpeptidation step. Earlier steps inbacterial cell wall biosynthesis have not been the target of action forcurrent commercial antibiotics, with the exception of fosfomycin. Theseearlier cytoplasmic steps involve biosynthetic conversions which requirethe MurA through MurF enzymes. Few inhibitors of the enzymes are knownto possess antibacterial activity.

Surprisingly, it has now been found that 3-aryl-4-hydroxyfuranonecompounds of formula I inhibit bacteria cell wall biosynthesis via theMur enzyme pathway. Advantageously, said hydroxyfuranone compounds areeffective therapeutic agents against bacterial infection or disease,particularly against infection or disease caused by resistant strains ofbacteria. Accordingly, the present invention provides3-aryl-4-hydroxyfuranone compounds of formula I

wherein

-   -   R is H;    -   R₁ is phenyl optionally substituted with one, two or three        halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,        C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl group each optionally substituted,        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted,        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted, or        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;    -   R₂ is phenyl optionally substituted with one, two or three        halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,        NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally        substituted with the proviso that only one of R₁ or R₂ may be an        optionally substituted phenyl group;        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each            optionally substituted; or        -   C₃-C₆cycloalkyl optionally substituted with one, two or            three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,            NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,            C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each            optionally substituted;    -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,        C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or        heteroaryl group each optionally substituted;    -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally        substituted C₁-C₆alkyl group; and    -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together        with the atom to which they are attached to form an optionally        substituted 5- to 7-membered ring optionally containing one or        two additional heteroatoms selected from N, O or S; or        a stereoisomer thereof, a tautomer thereof or a pharmaceutically        acceptable salt thereof.

As used in the specification and claims, the term halogen designates Br,Cl, I or F and the term aryl designates a carbocyclic aromatic ringsystem such as phenyl, naphthyl, anthracenyl or the like, preferablyphenyl. The term heteroaryl, as used herein, designates a 5- to10-membered aromatic ring system containing 1, 2 or 3 heteroatoms, whichmay be the same or different, selected from N, O or S. Such heteroarylring systems include pyrrolyl, azolyl, diazolyl, triazolyl, oxazolyl,thiazolyl, imidazolyl, furyl, thienyl, pyridyl, quinolinyl,isoquinolinyl, indolinyl, benzothienyl, benzofuranyl, benzodioxolyl,benzisoxazolyl or the like. The term haloalkyl as used herein designatesC_(n)H_(2n+1) group having from one to 2n+1 halogen atoms which may bethe same or different and the term haloalkoxy as used herein designatesan OC_(n)H_(2n+1) group having from one to 2n+1 halogen atoms which maybe the same or different.

In the specification and claims, when the terms C₁-C₆alkyl,C₃-C₁₂cycloalkyl, fluorenyl, aryl or heteroaryl are designated as beingoptionally substituted, the substituent groups which are optionallypresent may be one or more of those customarily employed in thedevelopment of pharmaceutical compounds or the modification of suchcompounds to influence their structure/activity, persistence,absorption, stability or other beneficial property. Specific examples ofsuch substituents include halogen atoms, nitro, cyano, thiocyanato,hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino,dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio,alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, phenyl, phenoxy,benzyl, benzyloxy, heteroaryl, cycloheteroalkyl or cycloalkyl groups,preferably halogen atoms, C₁-C₄ alkyl, halo(C₁-C₄)alkyl orhalo(C₁-C₄)alkoxy groups.

Typically, 0-3 substituents, preferably 1 or 2, the same or differentmay be present. When any of the foregoing substituents represents orcontains an alkyl substituent group, this may be linear or branched andmay contain up to 12, preferably up to 6, more preferably up to 4 carbonatoms.

Pharmaceutically acceptable salts may be any salt formed by a compoundof formula I and a pharmaceutically acceptable base such as organic orinorganic bases, e.g. alkali metal salts, (i.e., sodium, lithium, orpotassium) alkaline earth metal salts, ammonium salts, alkylammoniumsalts, dialkylammonium or trialkylammonium salts or the like.

Compounds of the invention may exist as one or more stereoisomers or inenolic tautomeric forms. The various stereoisomers include enantiomers,diastereomers, atropisomers and geometric isomers. Tautomers includeenols or ketones. One skilled in the art will appreciate that onestereoisomer or tautomer may be more active or may exhibit beneficialeffects when enriched relative to the other stereoisomer(s) or tautomeror when separated from the other stereoisomer(s) or tautomer.Additionally, the skilled artisan knows how to separate, enrich orselectively prepare said stereoisomers or tautomers. Accordingly, thepresent invention comprises compounds of formula I, the stereoisomersthereof, the tautomers thereof and the pharmaceutically acceptable saltsthereof. The compounds of the invention may be present as a mixture ofstereoisomers, individual stereoisomers, or as an optically active orenantiomerically pure form.

Preferred compounds of the invention are those compounds of formula Iwherein R₂ is an optionally substituted biphenyl or naphthyl group.Another group of preferred compounds are those compounds of formula Iwherein R₁ is phenyl substituted with one or two halogen orC₁-C₆haloalkyl groups. Further preferred compounds of the invention arethose compounds of formula I wherein R₁ is an optionally substitutedbiphenyl group and R₂ is an optionally substituted phenyl group.

More preferred compounds of the invention are those compounds of formulaI wherein R₁ is an optionally substituted phenyl group and R₂ is anoptionally substituted biphenyl or naphthyl group. Another group of morepreferred compounds are those compounds of formula I wherein R₁ isphenyl substituted with one or two halogen or C₁-C₆haloalkyl groups andR₂ is a biphenyl or naphthyl group optionally substituted with one ortwo halogen, OR₁₂, COR₁₃, C₁-C₆haloalkyl or C₁-C₆alkyl groups. Furthermore preferred compounds of the invention are those compounds of formulaI wherein R₁ is a biphenyl group substituted with one or two halogen andR₂ is an optionally substituted phenyl group.

Among the preferred compounds of the invention are:

-   (5Z)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)methylene]-3-(3,5-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-5-[(3′,4′-dichloro-1,1′-biphenyl-2-yl)methylene]-3-(3,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;-   5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3-chlorophenyl)-4-hydroxy-2(5H)-furanone;-   (5E)-5-[2′-chloro-2-methyl-1,1′-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{[2-methoxy-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene}furan-2(5H)-one;-   (5Z)-3-(3,5-dichlorophenyl)-5-[2,2′-dimethyl-1,1′-biphenyl-4-yl)methylene]-4-hydroxyfuran-2(5H)-one;-   5-{[2-chloro-3-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4-hydroxyfuran-2(5H)-one;-   3-(3-fluoro-4-biphenyl)-5-{[2-fluoro-5-(trifluoromethyl)phenyl]methylene}-4-hydroxyfuran-2(5H)-one;-   (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{[2-methyl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene}furan-2(5H)-one;-   (5Z)-5-[3-(benzyloxy)benzylidene]-3-(3,5-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-5-[(2′-acetyl-2-methyl-1,1′-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl)-4-hydroxyfuran-2(5H)-one;-   5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3,4-dichlorophenyl)-4-hydroxy-2(5H)-furanone;-   5-[Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3,5-dichlorophenyl)-4-hydroxy-2(5H)-furanone;-   3-(2-fluoro[1,1′-biphenyl]-4-yl)-4-hydroxy-5-{(Z)-[3-(trifluoromethyl)phenyl]-methylidene}furan-2(5H)-one;-   5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-2(5H)-furanone;-   (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-(1-napthylmethylene)furan-2(5H)-one;-   5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4-hydroxyfuran-2(5H)-one;-   5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(4′-ethoxy-4-biphenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{(4-methoxy-1-naphthyl)methylene]-furan-2(5H)-one;-   (5Z)-3-(3-chlorophenyl)-4-hydroxy-5-{[2-methyl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene]furan-2(5H)-one;-   (5Z)-5-[(3′-4′-dichloro-1,1′-biphenyl-3-yl)methylene]-3-(3,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;    a stereoisomer thereof;    a tautomer thereof; or    a pharmaceutically acceptable salt thereof.

The compounds of the invention may be conveniently prepared usingconventional synthetic methods and, if required, standard separation andisolation techniques. For example, compounds of formula I may beprepared by reacting a 3-bromo-4-alkoxy-furanone of formula II with analdehyde of formula III to give the 5-hydroxyalkyl-furanone of formulaIV; dehydrating the formula IV hydroxyalkylfuranone to give thecorresponding 5-methylenefuranone of formula V; reacting the formula Vcompound with a boronic acid derivative of formula VI to give the3-arylfuranone of formula VII; and hydrolyzing the formula VII compoundto the desired 4-hydroxyfuranone of formula I.

Alternatively, the formula II compound may be reacted with tributyl tinchloride to give the compound of formula VII. The formula VII compoundmay then be sequentially reacted with the aldehyde of formula III anddehydrated to give the compound of formula X; and said formula Xcompound may be reacted with an aryl halide of formula XI to give the4-alkoxy compound of formula VII. The formula VII compound may then behydrolyzed as described hereinabove to give the desired compound offormula I. The reactions are shown in flow diagram I wherein Rrepresents C₁-C₆alkyl, Hal represents Cl, Br or I and DMF designatesdimethyl formamide.

Compounds of formula I may also be prepared by reacting the formula II3-bromo-4-alkoxyfuranone with the boronic acid derivative of formula VIto give the 3-aryl-4-alkoxyfuranone of formula XII and converting saidformula XII furanone to the desired compound of formula I in a mannersimilar to that described hereinabove in flow diagram 1. The reaction isshown in flow diagram II wherein R is C₁-C₆alkyl.

Compounds of formula XII may also be prepared by reacting an aryl acetylchloride of formula XIII with an ester of glycolic acid to give thecompound of formula XIV; cyclizing said formula XIV compound in thepresence of a base, such as a metal alkoxide or metal amide, to give the4-hydroxyfuranone of formula XV; and alkylating the 4-hydroxy groupusing standard conditions such as Mitsunobu conditions to give theformula XII intermediate. The reaction is shown in flow diagram IIIwherein R represents C₁-C₆alkyl.

Compounds of formula I may also be prepared by reacting atriphenylphosphine salt of formula XVI with an aldehyde in the presenceof freshly prepared sodium ethoxide, as described in J. Chem. Soc.Perkin Trans I, 1567, 1985. The reaction is shown in flow diagram IVwherein Ph represents phenyl.

Compounds of formula I wherein R is other than H may be obtained bytreatment of the 4-hydroxy compound of formula I with an amine base inthe presence of an anhydride or acid chloride to give the correspondingester or by treatment of said 4-hydroxy compound of formula I with aninorganic base such as potassium carbonate with in the presence of analkyl, alkenyl, or benzyl halide to give the corresponding ether.

Advantageously, the formula I hydroxyfuranone compounds of the inventionwherein R is H and only one of R₁ and R₂ may be an optionallysubstituted phenyl group are effective as antibacterial agents.Accordingly, in one embodiment of the invention, there is provided amethod for the treatment of a bacterial infection or disease in apatient in need thereof which comprises providing to said patient apharmacologically effective amount of a compound of formula I.

The term, providing, as used herein with respect to providing a compoundor substance embraced by the invention, designates either directlyadministering such a compound or substance, or administering a prodrug,derivative or analog which forms an equivalent amount of the compound orsubstance within the body.

Bacterial infections include those infections caused by pathogenicbacteria such as the genera Staphylococcus; Streptococcus;Mycobacterium; Echerichia; Bacillus; Clostridium; Pasteurella;Haemophilus; Bordetella; or Pseudomonas; for example S. aureus, E.Faecalis, E. coli, S. pneumo, Staphylococcus, Enterococcus, or the likeand resistant bacteria such as methicillin resistant S. aureus,vancomycin resistant Enteroccocus, penicillin resistant S. pneumo, orthe like. Among the bacterial diseases which may be treated by themethod of invention are: meningitis, pharyngitis, pertussis, pneumonia,bronchitis, endocarditis, cholecystus, peritonitis, enteritis,enterocolitis, gastroenteritis, urethritis, arthritis, tracheitis,bacteremia, tuberculosis, folliculitis, mastitis, dermatitis,osteomyelitis, or the like.

The antibacterial compound of formula I may be provided to a patient inneed thereof by oral, parenteral, intravenous, or topical administrationor in any common manner known to be an effective administration of anantibacterial agent.

The pharmacologically effective amount administered in the treatment ofa specific bacterial disease may vary according to the specific diseasebeing treated, the size, age and response pattern of the patient, theseverity of the disease, the judgment of the attending physician or thelike. In general, effective amounts for daily oral administration may beabout 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the formula I compounds of the invention areprovided by administering the compound or a precursor thereof in a solidor liquid form, either neat or in combination with one or moreconventional pharmaceutical carriers or excipients. Accordingly, thepresent invention provides a pharmaceutical composition which comprisesa pharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove wherein R is H and onlyone of R₁ or R₂ may be an optionally substituted phenyl group.

In this embodiment of the invention, solid carriers suitable for use inthe pharmaceutical composition of the invention include one or moresubstances which may also act as flavoring agents, lubricants,solubilizers, suspending agents, fillers, glidants, compression aides,binders, tablet-disintegrating agents or encapsulating materials. Inpowders, the carrier may be a finely divided solid which is in admixturewith a finely divided compound of formula I. In tablets, the formula Icompound may be mixed with a carrier having the necessary compressionproperties in suitable proportions and compacted in the shape and sizedesired. Said powders and tablets may contain up to 99% by weight of theformula I compound. Solid carriers suitable for use in the compositionof the invention include calcium phosphate, magnesium stearate, talc,sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose,sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxesand ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensionsare suitable for intramuscular, intraperitoneal or subcutaneousinjection. Sterile solutions may also be administered intravenously.Inventive compositions suitable for oral administration may be in eitherliquid or solid composition form.

Ecto- and endoparasiticidal infection and infestation are a constantproblem in animal husbandry and in the care and raising of companionanimals. Important agronomic and companion animals such as cattle,sheep, horses, goats, pigs, camels, water buffalo, donkeys, rabbits,fallow deer, reindeer, minks, chinchillas, raccoons, chickens, geese,turkeys, ducks, dogs, cats or the like are prone to attack andinfestation by biting and sucking ectoparasitic insects such as Diptera,Muscidae or Siphonáptera. Helminthiases is a widespread disease found inmany farm and companion animals including cattle, sheep, swine, horses,poultry, fish, rabbits, goats, dogs, cats, or the like, as well as inhumans. Among the helminths, which cause significant damage aretrematodes such as Faciola hepatica or nematodes such asTrichostrongylus colubriformis, Haemonchus contortus and the like.Surprisingly, it has now been found that 3-aryl-4-hydroxyfuranonecompounds of formula I wherein R is H, COR₄ or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroarylgroup each optionally substituted, may be used to control, prevent,ameliorate or effectively treat infection and infestation ofectoparasites such as Diptera, Muscidae or Siphonáptera, orendoparasites such as helminths, including nematodes in animals andhumans. Advantageously, said hydroxyfuranone compounds may beparticularly effective for controlling, preventing or treating infectionor infestation of resistant strains of ecto- or endoparasites.Accordingly, in another embodiment of the invention, there is provided amethod for the prevention, amelioration or control of ecto- orendoparastic infection or infestation in a homeothermic animal whichcomprises administering to said animal a prophylactically,therapeutically, or pharmaceutically effective amount of a3-aryl-4-hydroxyfuranone compound of formula I

wherein

-   -   R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₁ is phenyl optionally substituted with one, two or three        halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,        C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl group each optionally substituted,        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted,        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted, or        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;    -   R₂ is phenyl optionally substituted with one, two or three        halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,        NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally        substituted;        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each            optionally substituted; or        -   C₃-C₆cycloalkyl optionally substituted with one, two or            three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,            NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,            C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each            optionally substituted;    -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,        C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or        heteroaryl group each optionally substituted;    -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally        substituted C₁-C₆alkyl group; and    -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together        with the atom to which they are attached to form an optionally        substituted 5- to 7-membered ring optionally containing one or        two additional heteroatoms selected from N, O or S; or        a stereoisomer thereof, a tautomer thereof or a pharmaceutically        acceptable salt thereof.

Preferred compounds of formula I useful in the animal health method ofinvention are those compounds of formula I wherein R₂ is phenylsubstituted with one or two halogen, C₁-C₆haloalkyl or cyano groups.Also preferred are those compounds of formula I wherein R₂ is anoptionally substituted biphenyl group. Another group of preferredcompounds useful in the animal health method of the invention are thosecompounds of formula I wherein R₁ is phenyl substituted with one or twohalogen, C₁-C₆haloalkyl or cyano groups. Further preferred compounds arethose compounds of formula I wherein R₁ is an optionally substitutedbiphenyl group.

Among the preferred compounds of formula I useful in the animal healthmethod of invention are:

-   5-(4-fluorobenzylidene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4-fluorobenzylidene-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4-fluorobenzylidene-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4-cyanobenzylidene-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4-trifluoromethylbenzylidene-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4-chlorobenzylidene-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4′-cyanobiphenyl-4-ylmethylene)-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4-cyanobenzylidene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-(4′-cyanobiphenyl-4-ylmethylene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4′-chlorobiphenyl-4-ylmethylene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4-cyanobenzylidene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one;-   5-(4-chlorobenzylidene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one;-   (5E)-(4′-cyanobiphenyl-4-ylmethylene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-(2-trifluoromethylbenzylidene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-(4-chlorobenzylidene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-(1,1′-biphenyl]-4-ylmethylidene-3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyfuran-2(5H)-one;-   (5Z)-(1,1′-biphenyl]-4-ylmethylidene-3-[3,5-bis(chloro)phenyl]-4-hydroxyfuran-2(5H)-one;-   (5Z)-(4′-chlorobiphenyl-4-ylmethylene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one;-   (5Z)-(4′-cyanobiphenyl-4-ylmethylene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one;-   Acetic acid    4-(4-chlorophenyl)-2-(4-cyanobenzylidene)-5-oxo-2,5-dihydrofuran-3-yl-ester;-   2,2 Dimethylpropionic acid    4-(4-chlorophenyl)-2-(4-cyanobenzylidene)-5-oxo-2,5-dihydrofuran-3-yl-ester;    a stereoisomer thereof;    a tautomer thereof; or    a pharmaceutically acceptable salt thereof.

Ectoparasitic insects which may be controlled, ameliorated or treated bythe animal health method of invention include Diptera, Muscidae orSiphonáptera, in particular, Diptera: Muscidae such as Musca autumnalis(face flies), Haemtobia irritans (horn flies) Stomoxys calcitrans(stable flies), heel flies, tsetse flies, blow flies or the like. Saidinsects are breeders of filth and vectors of disease and are seriousectoparasitic pests of important agronomic animals such as cattle,horses and sheep. Further, Diptera: Hippoboscidae (louse flies) such asMelophagus ovinus (sheep ked), which is a serious parasite of sheep areproblematic in animal production.

Among the Phthiraptera families known to be ectoparasites of animalsare: Trichodectidae such as Bovicola bovis (important cattle-bitinglouse), B. ovis (sheep-biting louse) or B. equi (horsebiting louse);Haematopinidae such as Haematopinus suis (hog louse), or H. asini (horsesucking louse); Linognathidae such as Linognathus stenopsis (goatsucking louse) or L. vitali (long-nosed cattle louse); or the like.

One of the Siphonáptera families known to infest companion animals isPulicìdae such as Archaeopsyllnìae (cat and dog fleas), Spilopsyllìnae(rabbit fleas), or the like.

Endoparasitic infections which may be controlled, ameliorated or treatedby the method of the invention include those Helminthiases infectionscaused by the class Trematoda, commonly known as flukes or flatworms orby the class Nematoda, commonly known as nematodes or roundworms. Themethod of the invention is particularly effective against infectioncaused by Trematoda, especially members of the genera Fasciola,Fascioloides, Paramphistomum, Dicrocoelium, Eurytrema, Ophisthorchis,Fascioiopsis, Echinostoma, or Paragonimus. The method of the inventionis uniquely effective against trematodes and may provide significantcontrol of the economically important Faciola hepatica, commonly knownas liver fluke. Helminthiases infection is also caused by a group ofworms referred to as nematodes. Nematodes cause serious damage to thewalls and tissues of the organs in which they reside, including theintestinal tract, heart, lungs and blood vessels, and are a primarycause of anemia. If left untreated they may result in death to theinfected host. The nematodes most commonly found to be the infectingagents of warm-blooded animals include Haemonchus, Ostertagia, Cooperia,Drofilaria, Oesphagastomum, Nematodirus and Dictyocaulus.

In addition to helmintic infection, the present method of invention isalso useful for the control of endoparasitic arthropod infestations suchas cattle grub. The method of invention is also effective againstinfection caused by nematodes such as, T. colubriformis, H. contortus,or the like.

Homeothermic animals suitable for use in the method of invention are allwarm-blooded animals susceptible to ecto- or endoparasitic infection orinfestation including farm animals such as cattle, sheep, swine, horses,poultry, rabbits, goats, or the like, preferably cattle, sheep, swine orhorses; companion animals such as dogs, cats, gerbils, rabbits, birds orthe like, preferably dogs or cats; or humans.

The effective amount of the formula I compound to be used in the animalhealth method of invention will vary according to the specific compoundused, the mode of application used, the identity of the parasite to becontrolled, the degree of infection or infestation, the extent of theparasite population, the nature of the target host, the weatherconditions or the like. Effective dosages may range from 0.1 mg/kg to100 mg/kg, preferably about 1.0 mg/kg to 50 mg/kg. Naturally, quantitiesof greater than effective amounts of said formula I compound may beadministered, but are not required for the protection of the targetanimals from the ecto- or endoparasite.

Compounds of formula I may be administered to the target homeothermicanimal orally, topically or parenterally, preferably orally. Forexample, the formula I 3-aryl-4-hydroxyfuranone compound may beadministered to said animal in or with their drinking water or as a feedadditive or in the form of a pill, tablet, bolus, implant, capsule ordrench. The formula I compound may also be administered topically byapplying said compound to the skin, hide or hair of the homeothermicanimal. Parenteral administration, i.e., intramural, intramuscular orsubcutaneous injection is also suitable for the inventive method.

In actual practice, the compounds of formula I are provided byadministering the compound or a precursor thereof in a solid or liquidform, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides an ecto- or endoparasiticidal composition whichcomprises a pharmaceutically acceptable carrier and an effective amountof a 3-aryl-4-hydroxyfuranone compound of formula I

wherein

-   -   R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₁ is phenyl optionally substituted with one, two or three        halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,        C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl group each optionally substituted,        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted,        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted, or        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;    -   R₂ is phenyl optionally substituted with one, two or three        halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,        NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally        substituted;        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each            optionally substituted; or        -   C₃-C₆cycloalkyl optionally substituted with one, two or            three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,            NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,            C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each            optionally substituted;    -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,        C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or        heteroaryl group each optionally substituted;    -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally        substituted C₁-C₆alkyl group; and    -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together        with the atom to which they are attached to form an optionally        substituted 5- to 7-membered ring optionally containing one or        two additional heteroatoms selected from N, O or S; or        a stereoisomer thereof, a tautomer thereof or a pharmaceutically        acceptable salt thereof.

In this embodiment of the invention, solid carriers suitable for use inthe ecto- or endoparasiticidal composition of the invention include oneor more substances which may also act as flavoring agents, lubricants,solubilizers, suspending agents, fillers, glidants, compression aides,binders, tablet-disintegrating agents or encapsulating materials. Inpowders, the carrier may be a finely divided solid which is in admixturewith a finely divided compound of formula I. In tablets, the formula Icompound may be mixed with a carrier having the necessary compressionproperties in suitable proportions and compacted in the shape and sizedesired. Said powders and tablets may contain up to 99% by weight of theformula I compound. Solid carriers suitable for use in the compositionof the invention include calcium phosphate, magnesium stearate, talc,sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose,sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxesand ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), dimethyl sulfoxide, alcohols(including monohydric alcohols and polyhydric alcohols, e.g., glycols)or their derivatives, or oils (e.g., fractionated coconut oil andarachis oil). For parenteral administration the carrier may also be anoily ester such as ethyl oleate or isopropyl myristate.

Ecto- or endoparasiticidal compositions of the invention which aresterile solutions or suspensions are suitable for intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions may also beadministered intravenously. Inventive compositions suitable for oraladministration may be in either liquid or solid composition form.

An ecto- or endoparasiticidal composition of the invention may be in theform of a pill, tablet, bolus, implant, capsule or drench, containingsufficient formula I compound to provide the treated animal with about0.01 mg/kg to 100 mg/kg of animal body weight per day of the formula Icompound. These dosage forms are prepared by intimately and uniformlymixing the active ingredient with suitable finely divided diluents,fillers, disintegrating agents and/or builders such as starch, lactose,talc, magnesium stearate, vegetable gums or the like. These unit dosageformulations may be varied according to the kind and size of the animalto be treated, the severity or type of infection encountered, the weightof the host animal, or the like.

For a parenteral composition, the formula I compound may be dispersed ina physiologically acceptable solvent for subcutaneous injection or itmay be dispersed in a fat or wax or mixture thereof containing an oil,buffer, surfactant, stabilizer, preservative and salt. Components usefulin these preparations include carbowax, aluminum monostearate gel,diethyl succinate, soya oil, glyercal dioleate, saline andcapric/caprylic triglycerides.

The formula I compound may also be applied topically to the largeranimals such as swine, sheep, cattle and horses and companion animalssuch as dogs and cats in the form of aqueous dips or sprays. For thisinventive composition, the active compound is generally prepared as awettable powder, emulsifiable concentrate, aqueous flowable or the like,which is mixed with water at the site of treatment and applied topicallyto the hide, skin or hair of the animal. Such sprays or dips usuallycontain about 0.5 ppm to 5000 ppm and preferably about 1 ppm to 3000 ppmof the compound.

Advantageously, the formula I compound may also be prepared as a pour-onformulation and poured on the backs of the animals such as swine,cattle, sheep, horses, poultry and companion animals. Such pour-oncompositions are generally prepared by dissolving, dispersing oremulsifying the formula I compound in a suitable nontoxicpharmacologically acceptable diluent for pour-on and administration. Thediluent must be compatible with the compound and should not be a sourceof irritation or damage to the animals hide, skin or hair. Such diluentsinclude vegetable oils, spreading oils, polyhydric alcohols, aliphaticor aromatic hydrocarbons, esters of fatty acids and lower alkyl ketones.

A typical pour-on formulation includes about 0.5% to 30% by weight ofthe formula I compound, about 30% to 60% by weight of an aliphatic oraromatic hydrocarbon, mono or polyhydric alcohol, lower alkyl ketone ormixtures thereof 0 to about 20% by weight of a vegetable or mineral oiland about 0.5% to 30% by weight of a spreading oil. Another typicalpour-on contains about 45% by weight of xylene about 15% by weight ofthe formula I hydroxy furanone compound, about 10% by weight of corn oilor mineral oil, about 25% by weight of cyclohexanone and about 5% byweight of other pharmacologically acceptable spreading agents, antifoamagents, surfactants or the like.

Surprisingly, the formula I compounds of the invention wherein R is H,COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,benzyl, aryl or heteroaryl group each optionally substituted, are usefulfor the control of plant parasitic nematodes and nematodes living freelyin soil. Accordingly, in a further embodiment of the invention, there isprovided a method for the control of nematode pests or parasites whichcomprises contacting said pests or parasites, their food supply, habitator breeding ground with a pesticidally or parasiticidally effectiveamount of a compound of formula I

wherein

-   -   R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₁ is phenyl optionally substituted with one, two or three        halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,        C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or        C₂-C₆alkynyl group each optionally substituted,        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted,        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted, or        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,            C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;    -   R₂ is phenyl optionally substituted with one, two or three        halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,        NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally        substituted;        -   biphenyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   naphthyl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally            substituted;        -   heteroaryl optionally substituted with one, two or three            halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,            NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,            C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each            optionally substituted; or        -   C₃-C₆cycloalkyl optionally substituted with one, two or            three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,            NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,            C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each            optionally substituted;    -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted;    -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,        C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or        heteroaryl group each optionally substituted;    -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally        substituted C₁-C₆alkyl group; and    -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,        haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally        substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together        with the atom to which they are attached to form an optionally        substituted 5- to 7-membered ring optionally containing one or        two additional heteroatoms selected from N, O or S; or        a stereoisomer thereof, a tautomer thereof or a pharmaceutically        acceptable salt thereof.

Plant parasitic nematodes include, but are not limited to, ectoparasitessuch as Xiphinema spp., Longidorus spp. and Trichodorus spp.;semi-parasites such as Tylenchulus spp.; migratory endoparasites such asPratylenchus spp., Radopholus spp. or Scutellonema spp.; sedentaryparasites such as Heterodera spp., Globodera spp. and Meloidogyne spp.;and stem and leaf endoparasites such as Ditylenchus sppp.,Aphelenchoides spp. or Hirshmaniella spp.

In agronomic practice, generally about 0.1 ppm to 10,000 ppm, preferablyabout 1.0 ppm to 5,000 ppm, of a formula I compound dispersed in wateror another liquid carrier, is effective when applied to plants or thesoil or water in which the plants are growing or are to be grown toprotect the plants from nematode attack or infestation. In thisembodiment of the invention the compounds of formula I may be formulatedas an emulsifiable concentrate, flowable concentrate, wettable powder,dilute spray, dry compacted granule, dust, suspension concentrate,microemulsion or any agronomic pesticidal composition which lends itselfto seed, soil, water or foliage application and provides the requisitenematode control and plant protection.

Accordingly, in this further embodiment of the invention, there isprovided a method for the protection of a growing or harvested plantfrom attack or infestation by nematode pests or parasites whichcomprises applying to the foliage of said plant or to the soil or waterin which it is growing a pesticidally effective amount of a compound offormula I as described hereinabove and wherein R is H, COR₄ or aC₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl orheteroaryl group each optionally substituted.

When applied to the foliage of plants or to the soil or water in whichthe plants are growing or are to be grown, effective amounts may be thatamount sufficient to provide about 0.1 kg/ha to 4.0 kg/ha of a compoundof formula I.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway.

Unless otherwise stated, all parts are parts by weight. The term NMRdesignates nuclear magnetic resonance. The terms THF and EtOAc designatetetrahydrofuran and ethyl acetate, respectively. The term DMF designatesdimethyl formamide and the term DMSO designates dimethylsulfoxide.

EXAMPLES Example 1 Preparation of3-Bromo-5-(hydroxynaphthalen-1-ylmethyl)-4-methoxy-5H-furan-2-one

A solution of N-isopropylcyclohexylamine (3.62 g, 4.22 mL, 28.22 mmol)in THF at −78° C. is treated with n-butyl lithium (2.1M in hexane, 13.2L), and stirred at −78° C. for 0.5 h. The resultant suspension is addeddropwise to a suspension of 3-bromo-4-methoxy-5H-furan-2-one (4.95 g,25.65 mmol) in THF at −78° C. The reaction mixture is stirred at −78° C.for 0.75 h, treated dropwise with a solution of 1-naphthylcarboxaldehyde(4.0 g, 25.65 mmol) in THF, stirred for 0.5 h at −78° C., allowed towarm to 0° C., quenched with saturated NH₄Cl and extracted with EtOAc.The extracts are combined, dried over MgSO₄ and concentrated in vacuo.The resultant red oil residue is passed through a pad of silica gelusing 100% hexanes and 80% EtOAc in hexanes as eluents to afford thetitle product as a yellow foam, 5.3 g (59% yield), identified by NMR andmass spectral analyses.

Example 2 Preparation of3-Bromo-4-methoxy-5-[(Z)-1-naphthylmethylidene]furan-2(5H)-one

A solution of3-bromo-5-(hydroxynaphthalen-1-ylmethyl)-4-methoxy-5H-furan-2-one (5.3g, 15.17 mmol) and triethylamine (9.22 g, 12.7 mL, 91.1 mmol) inanhydrous CH₂Cl₂ at 0° C. is treated dropwise with methane sulfonylchloride (6.96 g, 4.7 mL, 60.7 mmol), stirred for 0.5 h at 0° C.,allowed to warm to room temperature, treated sequentially withadditional triethylamine (4.64 g, 6.4 mL, 45.9 mmol) and methanesulfonyl chloride (3.55 g, 2.4 mL, 31 mmol), stirred until thedisappearance of starting material and diluted with EtOAc and water. Thephases are separated and the organic phase is dried over Na₂SO₄ andconcentrated in vacuo. The resultant residue is flash chromatographed(silica gel, 25% EtOAc in hexanes as eluent) to afford the title productas a yellow solid, 4.0 g (80% yield), mp 143-1481° C., identified by NMRand mass spectral analyses.

Example 3 Preparation of3-(4-Chlorophenyl)-4-methoxy-5-[(Z)-1-naphthylmethyl-idene]furan-2(5H)-one

A stirred mixture of 4-chlorophenylboronic acid (259 mg, 166 mmol),K₃PO₄ (962 mg, 4.53 mmol) and Pd(PPh₃)₄ (52 mg, 45.3 μmol) under N₂ istreated sequentially with of3-bromo-4-methoxy-5-[(Z)-1-naphthylmethylidene]furan-2(5H)-one (500 mg,1.51 mmol) and 9.3 mL of a 2:1 v/v mixture of dioxane/THF, heated at 90°C. until the disappearance of starting material by thin layerchromatography, cooled to room temperature, diluted with water andextracted with EtOAc. The extracts are combined, dried over MgSO₄ andconcentrated in vacuo. The resultant residue is purified by flashchromatography (silica gel, 25% EtOAc in hexanes as eluent) to affordthe title product as a yellow solid, 380 mg (69% yield), identified byNMR and mass spectral analyses.

Example 4 Preparation of3-(4-Chlorophenyl)-4-hydroxy-5-[(Z)-1-naphthylmethylidene]-furan-2-(5H)-one

A stirred mixture of3-(4-chlorophenyl)-4-methoxy-5-[(Z)-1-naphthylmethyl-idene]furan-2(5H)-one(380 mg, 0.998 mmol) and LiBr (86.6 mg, 0.998 mmol) in DMF is heated at150° C. for 10 min., cooled to room temperature, poured into 5 mL H₂SO₄,diluted with water and extracted with EtOAc. The extracts are combined,washed with water, dried over Na₂SO₄ and concentrated in vacuo. Theresultant oil residue is passed through a silica gel pad, using agradient elution of 100% EtOAc to 9:1 EtOAc:2.5% acetic acid inmethanol, to afford the title product as a rust-yellow solid, 270 mg(78% yield), mp 220°-224° C., identified by NMR and mass spectralanalyses.

Examples 5-96 Preparation of 3-Aryl-4-hydroxyfuranone Derivatives

Using essentially the same procedures described in Examples 1-4 andemploying a suitable arylcarboxaldehyde and the appropriate boronic acidderivative, the compounds shown on Table I are obtained and identifiedby NMR and mass spectral analyses. Unless otherwise noted, all compoundson Table I are the Z isomer.

TABLE I

Ex. mp No. R₁ R₂ ° C.  5 3-CF₃—C₆H₄ 1-naphthyl 100 (dec)  6 4-CH₃O—C₆H₄1-naphthyl 218-222  7 4-CH₃O—C₆H₄ 2-naphthyl   257-258.5  8 3-CF₃—C₆H₄2-naphthyl   239-240.8  9 4-CH₃O—C₆H₄ 4-biphenyl 266-269 10 3-CF₃—C₆H₄4-biphenyl   240-241.5 11 3-CF₃—C₆H₄ 4-biphenyl^(a) 230 12 3-CF₃—C₆H₄5-methylthien-2-yl 249-251 13 4-Cl—C₆H₄ 5-methylthien-2-yl^(a) 257 (dec)14 4-Cl—C₆H₄ 5-methylthien-2-yl^(b) 256-258 15 4-Cl—C₆H₄ cyclohexyl200-205 16 3-CF₃—C₆H₄ cyclohexyl^(c) 185-192 17 3-CF₃—C₆H₄ cyclohexyl  170-173.5 18 3-Cl—C₆H₄ 4-(2′-Cl—2CH₃O-biphenyl) 212-215 193,5-diCl—C₆H₃ 4-(2,2′-diCH₃O-biphenyl) 202-205 20 3,4-diCl—C₆H₃4-(2,2′-diCH₃O-biphenyl) 221-223 21 3,5-diCl—C₆H₃4-(2′-Cl-2-CH₃O-biphenyl) 223-225 22 3-Cl—C₆H₄ 4-(2-CH₃O-2′-CH₃- 176-180biphenyl) 23 3-Cl—C₆H₄ 4-(2′-CH₃O-2-CH₃- 223-224 biphenyl) 243,5-diCl—C₆H₃ 4-(2′-CH₃O-2-CH₃- 215-219 biphenyl) 25 3,5-diCl—C₆H₃4-(2-CH₃O-2′-CH₃- 140-150 biphenyl) 26 3-Cl—C₆H₄4-(2-CH₃-2′-CF₃-biphenyl) 218-222 27 3,5-diCl—C₆H₃4-(2-CH₃-2′-CF₃-biphenyl) 223-228 28 3-Cl—C₆H₄ 4-(2,2′-di-CH₃-biphenyl)219-222 29 3,5-diCl—C₆H₃ 4-(2,2′-di-CH₃-biphenyl) 228-231 30 3-Cl—C₆H₄4-(2′-Cl-2-CH₃-biphenyl) 211-215 (dec) 31 3,5-diCl—C₆H₃4-(2′-Cl-2-CH₃-biphenyl)^(c) 230-235 32 3-Cl—C₆H₄ 4-(2-CH₃O-2′-CF₃-219-222 biphenyl) 33 3,5-diCl—C₆H₃ 4-(2-CH₃O-2′-CF₃- 219-222 biphenyl)34 3,5-diCl—C₆H₃ 4-[3-F-(4-morpholin-4- 262-265 yl)phenyl] 35 3-Cl—C₆H₄1-(4-methoxynaphthyl)^(d) 233 (dec) 36 3,5-di-Cl—C₆H₃1-(4-methoxynaphthyl) 276-278 37 3-Cl—C₆H₄ 1-[(4-morpholin-4- 239-241yl)naphthyl] 38 3,5-diCl—C₆H₃ 1-[(4-morpholin-4- 253-256 yl)naphthyl] 393,5-diCl—C₆H₃ 4-(2-CH₃-2′CH₃SO₃- 221-229 biphenyl) 40 3,5-diCl—C₆H₃4-(2′-CH₃CO-2-CH₃- 223-225 biphenyl) 41 2-naphthyl 5-methylthien-2-yl144-145 (dec) 42 2-naphthyl 3-CF₃—C₆H₄ 185-189 43 2-naphthyl 4-Cl—C₆H₄243-250 44 2-naphthyl 1-naphthyl 205-207 45 2-naphthyl 4-biphenyl200-203 (dec) 46 1-naphthyl 4-Cl—C₆H₄ 235-237 47 1-naphthyl 1-naphthyl216-218 48 1-naphthyl 3-CF₃—C₆H₄ 173-176 49 1-naphthyl 3-CF₃—C₆H₄ ^(e)224-226 50 1-naphthyl 4-biphenyl 249-253 51 2-naphthyl Cyclohexyl205-208 52 2-naphthyl 2-naphthyl 285-290 53 4-Cl—C₆H₄ 4-biphenyl 282-28554 4-Cl—C₆H₄ 2-naphthyl 284-286 55 3-CF₃—C₆H₄ 4-(3′-CF₃-biphenyl)220-225 56 1-naphthyl 2-naphthyl 235-237 57 4-CH₃—C₆H₄4-(4′-CH₃-biphenyl) 261-265 58 2-F—C₆H₄ 4-(2′-F-biphenyl) 234-236 592-CN—C₆H₄ 4-(3′-CN-biphenyl) 259-263 60 2-CH₃—C₆H₄ 4-(2′-CH₃-biphenyl)164-167 61 2-CF₃—C₆H₄ 4-(2′-CF₃-biphenyl) 210-213 62 4-CN—C₆H₄4-(4′-CN-biphenyl) 238-240 63 3,5-di-Cl—C₆H₃ 4-(3′,5′-di-Cl-biphenyl)236-240 64 4-Cl—C₆H₄ 4-(4′-Cl-biphenyl) 276-280 65 2,4-di-Cl—C₆H₄4-biphenyl 252-256 66 3,4-di-Cl—C₆H₄ 4-biphenyl 265-269 673,5-di-Cl—C₆H₃ 4-biphenyl 279-280 68 3,5-di-Cl—C₆H₃ 4-biphenyl 232-23569 3-Cl—C₆H₄ 4-biphenyl 248-250 70 3,5-di-Cl—C₆H₃ 1-naphthyl 244-245 714-CF₃—C₆H₄ 1-naphthyl 245-247 72 3-CH₃O—C₆H₄ 1-naphthyl 214-216 734-[(1Z)CNOH—C₆H₄] 1-naphthyl^(f) 209-211 74 4-CO₂CH₃—C₆H₄ 1-naphthyl242-244 75 3-CO₂C₂H₅—C₆H₄ 1-naphthyl^(g) 169-171 76 3-CHO—C₆H₄1-naphthyl 220-221 77 3-CNOH—C₆H₄ 1-naphthyl 213-215 78 4-Cl—C₆H₄ 1-[(4-228 dimethylamino)naphthyl] 79 3,5-di-Cl—C₆H₃ 1-[(4- 168-194dimethylamino)naphthyl] 80 3,5-di-Cl—C₆H₃ 1-[(4- 167-172dimethylamino)naphthyl]^(h) 81 4-CF₃—C₆H₄ 1-[(4- 234-237dimethylamino)naphthyl] 82 3-CF₃—C₆H₄ 3-CF₃—C₆H₄ 221-224 83 4-Cl—C₆H₄3-CF₃—C₆H₄ 216-220 84 4-CH₃O—C₆H₄ 3-CF₃—C₆H₄ 200-226 (dec) 85 4-Cl—C₆H₄4-Cl—C₆H₄ 261-264 86 3-CF₃—C₆H₄ 4-Cl—C₆H₄ 233-236 87 4-CH₃O—C₆H₄4-Cl—C₆H₄ 272-275 88 4-CH₃O—C₆H₄ 4-CH₃O—C₆H₄ 245 89 4-CH₃O—C₆H₄4-CH₃O—C₆H₄ ^(a) 163-167 90 3-CF₃—C₆H₄ 4-CH₃O—C₆H₄ 221-225 913,5-diCl—C₆H₃ 4-[3-F-(4-piperizin-4-yl-1- 246-249ethylcarboxylate)phenyl] 92 3-Cl—C₆H₄ 4-[3-F-(4-piperizin-4-yl-1-226-228 ethylcarboxylate)phenyl] 93 3,5-diCl—C₆H₃ 3-(benzyloxy)phenyl198-200 94 3,5-diCl—C₆H₃ 2-(benzyloxy)phenyl — 95 3,5-diCl—C₆H₃4-{3-Cl-[4-(2- 259-261 Cl—C₆H₄)piperazin-1- yl]phenyl} 96 3,5-diCl—C₆H₃3-{[(2R)2- 226 methylcarboxylate]- piperidinyl-1- carbonyl}phenyl^(a)4.25:1 E:Z isomer mixture ^(b)3.5:1 Z:E isomer mixture ^(c)E isomer^(d)3:1 Z:E isomer mixture ^(e)7.1 E:Z isomer mixture ^(f)1:1.55 E:Zisomer mixture ^(g)E Z isomer mixture ^(h)1:1 E:Z isomer mixture

Example 97 Preparation of5-{Hydroxy-[2-(trifluoromethyl)phenyl]methyl}-4-methoxy-5H-furan-2-one

A mixture of 4-methoxy-5H-furan-2-one (2.00 g, 17.5 mmol),2-(trifluoromethyl)-benzaldehyde (3.05 g, 17.5 mmol) and lithiumhydroxide monohydrate (0.148 g, 3.53 mmol) in acetonitrile is stirred atroom temperature for 0.5 h, treated with water, stirred for 0.5 h andconcentrated in vacuo. The resultant residue is diluted with water andfiltered. The filtercake is dried in vacuo to give the title product asa white solid, 3.00 g (59% yield), mp 126-128° C., identified by NMR andmass spectral analyses.

Example 98 Preparation of3-Bromo-4-methoxy-5-{(Z)-[2-(trifluoromethyl)benzylidene]}-5H-furan-2-one

A stirred solution of5-{hydroxy-[2-(trifluoromethyl)phenyl]methyl}-4-methoxy-5H-furan-2-one(2.9 g, 10.1 mmol) in acetonitrile at room temperature is treateddropwise with bromine (0.52 ml, 10.1 mmol), stirred for 24 h andconcentrated in vacuo. The resultant residue is diluted with CH₂Cl₂ andtriethylamine (4.25 ml), cooled in an ice bath, treated with methanesulfonyl chloride (1.6 ml), stirred for 0.5 h at ice bath temperatures,allowed to warm to room temperature for 2 h and diluted with EtOAc andwater. The organic phase is separated, dried over MgSO₄ and concentratedin vacuo. This residue is flash chromatographed (SiO₂, hexane/EtOAc aseluent) to afford the title product as a white solid, 0.20 g (6% yield),mp 136-138° C., identified by NMR and mass spectral analyses.

Example 99 Preparation of3-[1,1′-Biphenyl]-4-yl-4-hydroxy-5-{(Z)-[2-(trifluoromethyl)benzylidene]}-5H-furan-2-one

Using essentially the same procedures described in Examples 3 and 4hereinabove and employing the 3-bromofuranone of Example 83 and4-biphenylboronic acid as reagents, the title product is obtained aswhite solid, mp 228-230° C., identified by NMR and mass spectralanalyses.

Examples 100-162 Preparation of 3-Aryl-4-hydroxyfuranone Derivatives

Using essentially the same procedures described in Examples 1-4 and82-84 and employing a suitable arylcarboxaldehyde and appropriateboronic acid derivative, the compounds shown on Table II are obtainedand identified by NMR and mass spectral analyses. Unless otherwisenoted, all compounds on Table II are the Z isomer.

TABLE II

Ex. mp No. R₁ R₂ ° C. 100 4-biphenyl cyclohexyl 204-207 101 4-biphenyl3-pyridyl 252-255 102 4-biphenyl 1-naphthyl 226-230 103 4-biphenyl2-naphthyl 266-270 104 4-biphenyl 5-methylthien-2-yl 235-240 1054-biphenyl 4-CF₃—C₆H₄ 250-255 106 4-(2-F-biphenyl) 3-CF₃—C₆H₄ 222-226107 4-(2-F-biphenyl) 2-CF₃—C₆H₄ 224-228 108 3-biphenyl 3-CF₃—C₆H₄210-212 109 3-biphenyl 3-F-5-CF₃—C₆H₃ — 110 4-(2-F-biphenyl)3-F-5-CF₃—C₆H₃ — 111 4-(4′-propylbiphenyl) 3-F-5-CF₃—C₆H₃ — 1123-biphenyl 3-F-5-CF₃—C₆H₃ — 113 4-biphenyl 2-Cl-3-CF₃—C₆H₃ — 1144-(2-F-biphenyl) 2-Cl-3-CF₃—C₆H₃ — 115 4-(4′-propylbiphenyl)2-Cl-3-CF₃—C₆H₃ — 116 4-(4′-t-butylbiphenyl) 2-Cl-3-CF₃—C₆H₃ — 1174-(4′-C₂H₅O-biphenyl) 2-Cl-3-CF₃—C₆H₃ — 118 4-biphenyl 2-F-5-CF₃—C₆H₃ —119 4-(2-F-biphenyl) 2-F-5-CF₃—C₆H₃ — 120 4-(4′-t-butylbiphenyl)2-F-5-CF₃—C₆H₃ — 121 3-biphenyl 2-F-5-CF₃—C₆H₃ — 1224-(4′-C₂H₅O-biphenyl 2-F-5-CF₃—C₆H₃ — 123 4-(4′-t-butylbiphenyl)4-Cl-3-CF₃—C₆H₃ — 124 4-(4′-C₂H₅O-biphenyl) 4-Cl-3-CF₃—C₆H₃ — 1254-biphenyl 2-Cl-5-CF₃—C₆H₃ — 126 4-(2-F-biphenyl) 2-Cl-5-CF₃—C₆H₃ — 1274-(4′-propylbiphenyl) 2-Cl-5-CF₃—C₆H₃ — 128 4-(4′-t-butylbiphenyl)2-Cl-5-CF₃—C₆H₃ — 129 4-(4′-C₂H₅O-biphenyl) 2-Cl-5-CF₃—C₆H₃ — 1304-biphenyl 3-CF₃—C₆H₄ — 131 4-(4′-propylbiphenyl) 3-CF₃—C₆H₄ — 1324-(4′-t-butylbiphenyl) 3-CF₃—C₆H₄ — 133 4-(4′-C₂H₅O-biphenyl) 3-CF₃—C₆H₄— 134 3-Cl—C₆H₄ 3-(3′-Cl-biphenyl) 191-193 135 3,4-di-Cl—C₆H₃3-(3′,4-di-Cl-biphenyl) 214-216 136 3,5-di-Cl—C₆H₃3-(3′,5′-di-Cl-biphenyl) 233-236 137 4-Cl—C₆H₄ 2-(4′-Cl-biphenyl)230-232 138 4-(2-F-biphenyl) 4-Cl—C₆H₄ 255-258 139 4-biphenyl 4-Cl—C₆H₄280-282 140 3-Cl—C₆H₄ 2-(3′-Cl-biphenyl) 218-221 141 3,4-di-Cl—C₆H₃2-(3′,4′-di-Cl-biphenyl) 237-239 142 4-[3-F-(4-morpholin-2-Cl-5-CF₃—C₆H₃ 232-234 4-yl)-C₆H₃] 143 benzo[b]thiophen-3-yl 4-biphenyl270 144 thiophen-2-yl 4-biphenyl 213 (dec) 145 4-CN—C₆H₄ 2-CF₃—C₆H₄147-150 146 4-F—C₆H₄ 2-CF₃—C₆H₄ 147-150 147 3-biphenyl 3-CF₃—C₆H₄210-212 148 2,5-di-CH₃C₆H₃ 2-Cl-5-CF₃—C₆H₃ — 149 3-CH₃C₆H₄2-Cl-5-CF₃—C₆H₃ — 150 4-isopropyl-C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 1513-isopropyl-C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 152 4-C₂H₅—C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 1534-CH₃—C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 154 3,4-di-CH₃—C₆H₃ 2-Cl-3-CF₃—C₆H₃ — 1553-CH₃—C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 156 C₆H₅ 3-CF₃—C₆H₄ 224-226 1573,5-di-Cl—C₆H₃ 3-{[(S)-1- 175-178 phenethyl]NHSO₂}—C₆H₄ 1583,5-di-Cl—C₆H₃ 3-{[(R)-1- 195-198 phenethyl]urea}-C₆H₄ 1593,5-di-Cl—C₆H₃ 3-{[(S)-1- 210-212 phenethyl]urea}-C₆H₄ 1603,5-di-Cl—C₆H₃ 2-Cl-5-CF₃—C₆H₃ 244-247 161 3,5-di-Cl—C₆H₃4-benzyloxy-3-CH₃O—C₆H₃ 105-110 162 3,5-di-Cl—C₆H₃3-benzyloxy-4-CH₃O—C₆H₃ 214 (dec)

Example 163 Preparation of(5E)-(4-cyanobenzylidine)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one

Step 1: A solution of 4-bromobenzonitrile (9.22 grams, 50.7 mmol),copper(I)iodide (0.63 grams, 3.3 mmol), triphenylphosphine (2.0 grams,7.6 mmol) and palladium acetate (0.56 grams, 2.5 mmol) in 30 ml of THFis purged with nitrogen, treated with 20 ml of N-butylamine (202.4mmol), stirred for 10 minutes, treated with 3.0 ml of propargyl alcohol(50.7 mmol), stirred at ambient temperatures for 3 h, treated withsilica gel (20 grams) and concentrated under reduced pressure. Theresidue is purified by flash column chromatography (50% ether in hexane)to afford the desired product A in 91% yield (7.30 grams).

Reference: U.S. Pat. No. 6,239,280

Step 2: A mixture of the product A from above (7.00 grams, 44.6 mmol)and KOH (0.5 grams, 8.9 mmol) in acetonitrile is treated dropwise over30 minutes with n-butylthiol 5.9 ml, 55.3 mmol), stirred for anadditional 30 minutes, treated with silica gel (15 grams) andconcentrated under reduced pressure. The residue is purified by flashcolumn chromatography (50% ether in hexane) to give the desired productB in 71% yield (7.85 grams).

Reference: Tetrahedron Lett., 41, 141, 2000.

Step 3: A solution of the product B from above (7.50 grams, 30.4 mmol)in ethanol and 20 ml of 1N sulfuric acid is heated at 75° C. for 48hours, cooled to ambient temperature and diluted with a mixture of ethylacetate and brine. The organic phase is separated and dried overanhydrous sodium sulfate. Silica gel (10 grams) is added and theresultant mixture is concentrated under reduced pressure. The residue ispurified by flash column chromatography (100% CH₂Cl₂) to give thedesired product C in 72% yield (3.85 grams).

Reference: Tetrahedron Lett., 41, 141, 2000.

Step 4: A 2 M solution of lithium diisopropylamine (LDA) (27.5 ml, 55mmol) is added to 100 ml of THF at −78° C. A solution of the product Cfrom above (3.85 grams, 22 mmol) in 50 ml of THF is added to the LDAsolution over 30 minutes at

−78° C., stirred for another hour at −78° C., treated portionwise withcarbonyl diimidazole (8.91 grams, 55 mmol) over 30 minutes, stirred foran additional 2 hours at −78° C., warmed to ambient temperature, stirredan additional hour, diluted with 60 ml of 3 M sulfuric acid and 100 mlof brine. The organic phase is separated and dried over anhydrous sodiumsulfate. Silica gel (10 grams) is added and the mixture is concentratedunder reduced pressure. Flash column chromatography (80% acetone inhexane) of the residue gives the desired product D in 37% yield (1.65grams).

Reference: Tetrahedron Lett,. 20, 4517, 1979.

Step 5: A solution of the product D from above (3.30 grams, 16.4 mmol)and potassium carbonate 2.04 grams, 14.8 mmol) in acetone is treatedwith dimethyl sulfate (3.5 ml), heated at reflux temperature for 1.5hours, cooled to ambient temperature, treated with silica gel (5 grams)and concentrated under reduced pressure. Flash column chromatography(100% CH₂Cl₂) of the residue gives the desired product E in 64% yield(2.25 grams).

Reference: J. Chem. Soc. Perkin Trans. I, 1567, 1985.

Step 6: The product E from above (1.80 grams, 8.37 mmol) is dissolved in1,2-dichloroethane heated to reflux temperature treated portionwise withN-bromo-succinimide (1.60 grams, 8.96 mmol) and AIBN (50 mg) over a 2hour period, cooled and diluted with a mixture of CH₂Cl₂ and water. Theorganic phase is separated, dried over anhydrous sodium sulfate, treatedwith silica gel (5 grams) and concentrated under reduced pressure. Flashcolumn chromatography (100% CH₂Cl₂) of the residue gives the desiredproduct F in 67% yield (1.65 grams).

Reference: J. Chem. Soc. Perkin Trans. I, 1567, 1985.

Step 7: The product F from above (1.65 grams, 5.63 mmol) is dissolved intoluene and heated to 85° C., treated dropwise with a solution oftriphenylphosphine (1.85 grams, 7.04 mmol) in toluene, stirred at 85° C.for 2 hours, cooled and filtered. The solid filtercake is dried undersuction to give the desired product G in 85% yield (2.23 grams).

Reference: J. Chem. Soc. Perkin Trans. I, 1567, 1985.

Step 8: A solution of sodium (0.11 grams, 4.77 mmol) in ethanol istreated sequentially with 4′-cyano-4-phenyl benzaldehyde (1.03 grams,4.96 mmol) and the product G from above (2.00 grams, 4.34 mmol), stirredat ambient temperature for 2 hours, and diluted with a mixture of waterand toluene. The aqueous layer is separated, acidified to pH 1.0 with 4N HCl and filtered. The solid filtercake is suction dried, washed twicewith toluene and suction dried again to give the title product as a 7 to1 mixture of Z to E isomers in 41% yield (0.68 grams). The two isomersmay be separated by washing the E isomer out with chloroform.

Reference: J. Chem. Soc. Perkin Trans. I, 1567, 1985.

Examples 164-226 Preparation of 3-Aryl-4-hydroxyfuranone Derivatives

Using essentially the same procedures described in Example 163hereinabove and employing a suitable arylcarboxaldehyde and appropriateWittig reagent, and alkylating or acylating the 4-hydroxy group usingconventional techniques, the compounds shown on Table III are obtainedand identified by NMR and mass spectral analyses. Mass ions of thecompounds are either M−H/M+H/M+Na or M+ depending upon method used.Example 174 is M-CO₂tBu. Unless otherwise noted, all compounds on TableIII are the Z isomer.

Table III

Ex. Mass No. R R1 R2 Ion 164 H 4-CN—C₆H₄* 4-(4′-CN-biphenyl) 389 165 H4-CN—C₆H₄** 4-Cl—C₆H₄ 323 166 H 4-CN—C₆H₄** 4-CN—C₆H₄ 314 167 H4-CN—C₆H₄** 4-(4′-Cl-biphenyl) 398 168 H 4-Cl—C₆H₄ 4-(4′-CN-biphenyl)399 169 H 4-Cl—C₆H₄* 4-(4′-CN-biphenyl) 399 170 H 4-Cl—C₆H₄** 4-CN—C₆H₄323 171 H 4-Cl—C₆H₄** 3-Cl—C₆H₄ 332 172 H 3-CF₃—C₆H₄ 4-Cl—C₆H₄ *** 173CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 338 174 CO₂t-Bu 4-Cl—C₆H₄** 4-CN—C₆H₄ 322 175CO₂C₆H₅ 4-Cl—C₆H₄** 4-CN—C₆H₄ 450 176 CO₂CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 388177 CH₂CH═CH₂ 4-Cl—C₆H₄** 4-CN—C₆H₄ 364 178 H 4-CF₃—C₆H₄** 4-CN—C₆H₄ 356179 H 4-CF₃—C₆H₄** 4-Cl—C₆H₄ 367 180 H 4-CF₃—C₆H₄** 4-CF₃—C₆H₄ 399 181 H4-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 441 182 H 4-CF₃—C₆H₄**4-(4′-CN-biphenyl) 432 183 H 4-CF₃—C₆H₄** 4-F—C₆H₄ 349 184 H 4-F—C₆H₄**4-CN—C₆H₄ 306 185 H 4-F—C₆H₄** 4-Cl—C₆H₄ 315 186 H 4-F—C₆H₄** 4-CF₃—C₆H₄349 187 H 4-F—C₆H₄** 4-F—C₆H₄ 299 188 H 4-F—C₆H₄ 4-(4′-CN-biphenyl) 382189 H 4-F—C₆H₄** 4-(4′-Cl-biphenyl) 391 190 H 3-Cl—C₆H₄** 4-CN—C₆H₄ 322191 H 3-Cl—C₆H₄** 4-Cl—C₆H₄ 331 192 H 3-Cl—C₆H₄** 4-CF₃—C₆H₄ 365 193 H3-Cl—C₆H₄** 4-(4′-Cl-biphenyl) 407 194 H 3-Cl—C₆H₄** 4-(4′-CN-biphenyl)398 195 H 3-Cl—C₆H₄** 4-F—C₆H₄ 315 196 H 3-CF₃—C₆H₄** 4-CN—C₆H₄ 356 197H 3-CF₃—C₆H₄** 4-F—C₆H₄ 349 198 H 3-CF₃—C₆H₄** 4-CF₃—C₆H₄ 399 199 H3-CF₃—C₆H₄** 4(4′-Cl-biphenyl) 441 200 H 3-CF₃—C₆H₄** 4(4′-CN-biphenyl)432 201 H 3-CN—C₆H₄** 4-CN—C₆H₄ 313 202 H 3-CN—C₆H₄** 4-Cl—C₆H₄ 322 203H 3-CN—C₆H₄** 4-CF₃—C₆H₄ 356 204 H 3-CN—C₆H₄** 4-(4′-Cl-biphenyl) 398205 H 3-CN—C₆H₄** 4-(4′-CN-biphenyl) 387 206 H 3-CN—C₆H₄** 4-F—C₆H₄ 306207 H 4-CN—C₆H₄** 4-CF₃—C₆H₄ 356 208 H 4-CN—C₆H₄** 3-CF₃—C₆H₄ 356 209 H4-CN—C₆H₄** 4-(4′-CF₃-biphenyl) *** 210 H 4-CN—C₆H₄** 4-F—C₆H₄ 306 211 H4-Cl—C₆H₄** 4-CF₃—C₆H₄ 365 212 H 4-Cl—C₆H₄** 2-CF₃—C₆H₄ 365 213 H4-Cl—C₆H₄** 4-(4′-CF₃-biphenyl) 441 214 H 4-Cl—C₆H₄** 4-F—C₆H₄ 315 215 H4-(4′-Cl-biphenyl)** 4-CF₃—C₆H₄ 441 216 H 4-(4′-Cl-biphenyl)** 4-CN—C₆H₄398 217 H 4-(4′-Cl-biphenyl)** 4-Cl—C₆H₄ 409 218 H 4-(4′-CN-biphenyl)**4-CF₃—C₆H₄ 389 219 H 4-(4′-CN-biphenyl)** 4-CN—C₆H₄ 432 220 H4-(4′-CN-biphenyl)** 4-Cl—C₆H₄ 398 221 H 4-Cl—C₆H₄** 3,4-diCl—C₆H₃ ***222 H 4-Cl—C₆H₄** 2,4-diCl—C₆H₃ *** 223 H 4-Cl—C₆H₄** 3-F-4-CF₃—C₆H₃ ***224 H 4-CN—C₆H₄** 3,4-diCl—C₆H₃ *** 225 H 4-CN—C₆H₄** 2,4-diCl—C₆H₃ ***226 H 4-CN—C₆H₄** 3-F-4-CF₃—C₆H₃ *** 227 H 4-F—C₆H₄** 4-OCF₃—C₆H₄ ***228 H 4-CN—C₆H₄** 4-OCF₃—C₆H₄ *** 229 H 4-CN—C₆H₄** 4-OCHF₂—C₆H₄ *** 230H 4-CN—C₆H₄** 4-OCF₂CHF₂—C₆H₄ *** 231 H 4-CN—C₆H₄**5-chlorothiophen-2-yl *** 232 H 4-CN—C₆H₄** 2,2difluoro-1,3-dioxol- ***C₆H₃-5-yl 233 H 4-OCF₃—C₆H₄** 3,5-diCl—C₆H₃ 417 234 H 4-OCF₃—C₆H₄**3,4-diF—C₆H₃ 384 235 H 4-OCF₃—C₆H₄** 4-n-propoxy-C₆H₄ 406 236 H4-OCF₃—C₆H₄** 3,4-diCl—C₆H₃ 417 237 H 4-OCF₃—C₆H₄** 3-F-4-CF₃—C₆H₃ 434238 H 4-OCF₃—C₆H₄** 5-chlorothiophen-2-yl 389 239 H 4-OCF₃—C₆H₄**thiophen-2-yl 354 240 H 4-OCF₃—C₆H₄** 4-phenoxy-C₆H₄ 440 241 H4-OCF₃—C₆H₄** pyridine-3-yl 349 242 H 4-OCF₃—C₆H₄** 4-OCF₃—C₆H₄ 432 243H 4-OCF₃—C₆H₄** 4-F—C₆H₄ 366 244 H 4-OCF₃—C₆H₄** 4-CN—C₆H₄ 373 245 H4-OCF₃—C₆H₄** 4-Cl—C₆H₄ 383 246 H 4-OCF₃—C₆H₄** 4-OCHF₂—C₆H₄ 414 247 H4-OCF₃—C₆H₄** 2-F-5-CF₃—C₆H₃ 434 248 H 4-OCF₃—C₆H₄** 4-CF₃—C₆H₄ 416 249H 4-OCF₃—C₆H₄** 3-F-5-CF₃—C₆H₃ 434 250 H 4-OCF₃—C₆H₄** 2-F-4-CF₃—C₆H₃434 251 H 4-OCF₃—C₆H₄** 4-OCF₂CHF₂—C₆H₄ 464 252 H 4-OCF₃—C₆H₄**2,2difluoro-1,3-dioxol- 428 C₆H₃-5-yl 253 H 4-OCF₃—C₆H₄** pyridine-4-yl349 254 H 4-OCF₃—C₆H₄** pyridine-2-yl 349 255 H 4-OCF₃—C₆H₄**3-Br-pyridine-2-yl 428 256 H 4-OCF₃—C₆H₄** 4-(4-F-phenyl)-pyridin-3-yl442 257 H 4-OCF₃—C₆H₄** 4-(thiophen-2-yl)- 431 pyridin-3-yl 258 H4-OCF₃—C₆H₄** 4-(4-OCF₃-phenyl)- 509 pyridin-3-yl 259 H 4-OCF₃—C₆H₄**4-(5-Cl-thiophen-2-yl)- 465 pyridin-3-yl 260 H 4-OCF₃—C₆H₄**4-(4-Cl-phenyl)-pyridin-3-yl 460 261 H 4-OCF₃—C₆H₄**4-(3-Cl-phenyl)-pyridin-3-yl 460 262 H 4-OCF₃—C₆H₄** 4-Br-pyridine-3-yl428 263 H 4-OCF₃—C₆H₄** 3-Cl-pyridine-4-yl 384 264 H 4-OCF₃—C₆H₄**4-cyclopropylmethoxy-C₆H₄ 418 265 H 4-OCF₃—C₆H₄**4-(5-Cl-thiophen-2-yl)-C₆H₄ 464 266 H 4-OCF₃—C₆H₄**2-methyl-1H-imidazol-4-yl 352 267 H 4-OCF₃—C₆H₄** 5-chloro-1,3-dimethyl-401 1H-pyrazol-4-yl 268 H 4-OCF₃—C₆H₄** 5-methyl-1-o-tolyl-1H- 442pyrazol-4-yl 269 H 4-OCF₃—C₆H₄** 2-phenyl-1H-imidazol-4-yl 414 270 H4-OCF₃—C₆H₄** 2-Cl-pyridine-3-yl 384 271 H 4-OCF₃—C₆H₄**4-chloro-1-methyl-1H- 387 pyrazol-3-yl 272 H 4-OCF₃—C₆H₄**5-(4-F-3-CF₃-phenyl)- 500 furan-2-yl 273 H 4-OCF₃—C₆H₄**5-chloro-1-methyl-3- 455 trifluoromethyl-1H- imidazol-3-yl 274 H4-OCF₃—C₆H₄** 5-bromo-1-methyl-1H- 431 imidazol-3-yl 275 H 4-OCF₃—C₆H₄**1-(4-methoxyphenyl)-5- 458 methyl-1H-pyrazol-4-yl 276 H 4-OCF₃—C₆H₄**1-(4-fluorophenyl)-5- 446 methyl-1H-pyrazol-4-yl 277 H 4-OCF₃—C₆H₄**1-(phenyl)-5-methyl- 428 1H-pyrazol-4-yl 278 H 4-OCF₃—C₆H₄**2-methanesulfanyl- 406 nicotinonitrile 279 H 4-OCF₃—C₆H₄**5-bromo-furan-2-yl 417 280 H 4-OCF₃—C₆H₄** 6-phenoxy-pyridin-3-yl 441281 H 4-OCF₃—C₆H₄** 4-(1,2,4-triazol-1-yl)-C₆H₄ 415 282 H 4-OCF₃—C₆H₄**5-(pyridine-2-yl)- 431 thiphen-2-yl 283 H 4-OCF₃—C₆H₄**5-(6-morpholino-4-yl)- 434 pyridin-3-yl 284 H 4-OCF₃—C₆H₄**4-(4-methyl-piperazin- 446 1-yl)-C₆H₄ 285 H 4-OCF₃—C₆H₄**4-(thiophen-2-yl)-C₆H₄ 430 286 H 4-OCF₃—C₆H₄** 4-(pyrrol-1-yl)-C₆H₄ 413287 H 4-OCF₃—C₆H₄** 4-(4′-Cl-biphenyl) 459 288 H 4-OCF₃—C₆H₄**4-(4′-CN-biphenyl) 449 289 H 4-OCF₃—C₆H₄** 2,5-dimethyl-2H- 366pyrazol-3-yl 290 H thiophen-2-yl 4-CN—C₆H₄ 295 291 H thiophen-2-yl4-Cl—C₆H₄ 305 292 H thiophen-2-yl 4-CF₃—C₆H₄ 338 293 H5-chlorothiophen-2-yl 4-Cl—C₆H₄ 339 294 H 5-chlorothiophen-2-yl4-CN—C₆H₄ 330 295 H 5-chlorothiophen-2-yl 4-CF₃—C₆H₄ 373 296 H5-chlorothiophen-2-yl 4-OCF₃—C₆H₄ 389 297 H 5-chlorothiophen-2-yl4-OCHF₂—C₆H₄ 371 298 H 5-chlorothiophen-2-yl 3,4-diCl—C₆H₃ 374 299 H5-chlorothiophen-2-yl 3,4-diF—C₆H₃ 341 300 H 5-chlorothiophen-2-yl4-F-3-CF₃—C₆H₃ 391 301 H 5-chlorothiophen-2-yl 4-F—C₆H₄ 323 302 H5-chlorothiophen-2-yl 3-F-4-CF₃—C₆H₃ 391 303 H 5-chlorothiophen-2-yl4-(4′-Cl-biphenyl) 415 304 H 5-chlorothiophen-2-yl4-cyclopropylmethoxy-C₆H₄ 375 305 H 5-chlorothiophen-2-yl4-OCF₂CHF₂—C₆H₄ 421 306 H 5-chlorothiophen-2-yl 5-chlorothiophen-2-yl345 307 H 5-chlorothiophen-2-yl 4-Br-pyridine-3-yl 385 308 H5-chlorothiophen-2-yl 2,2difluoro-1,3-dioxol- 385 C₆H₃-5-yl 309 H5-chlorothiophen-2-yl 4-(4-Cl-phenyl)-pyridin-3-yl 416 310 H5-chlorothiophen-2-yl 4-(4-F-phenyl)-pyridin-3-yl 400 311 H5-chlorothiophen-2-yl 4-(4-OCF₃-phenyl)- 466 pyridin-3-yl 312 H5-chlorothiophen-2-yl 4-(5-Cl-thiophen-2-yl)- 422 pyridin-3-yl 313 H5-chlorothiophen-2-yl 4-(5-Cl-thiophen-2-yl)-C₆H₄ 421 314 H 4-Cl—C₆H₄**4-cyclopropylmethoxy-C₆H₄ *** 315 H 4-Cl—C₆H₄** 4-SCF₃—C₆H₄ *** 316 H4-Cl—C₆H₄** 2-methanesulfanyl- *** nicotinonitrile 317 H 4-Cl—C₆H₄**5-(4-F-3-CF₃-phenyl)- *** furan-2-yl 318 H 4-Cl—C₆H₄**6-phenoxy-pyridin-3-yl *** 319 H 4-Cl—C₆H₄** 1-(4-fluorophenyl)-5- ***methyl-1H-pyrazol-4-yl 320 H 4-CN—C₆H₄** 6-phenoxy-pyridin-3-yl *** 321H 4-CN—C₆H₄** 1-(4-fluorophenyl)-5- *** methyl-1H-pyrazol-4-yl 322 H4-CN—C₆H₄** 2-methanesulfanyl- *** nicotinonitrile *E isomer **Mixtureof Z and E isomers ***NMR analysis only

Example 323 Evaluation of the Inhibitory Activity of Test CompoundsAgainst Enzymes Which Catalyze Bacterial Cell Wall Biosynthesis

S. aureus and E. coli UDP-N-acetylalucosamine enolpyruvoyl Transferase,MurA

Preparation of Enzyme Solution:

The enzyme solution is prepared by admixing the following:

50 mM Tris/HCl pH 8.0, 500 ml 1 M Tris, 5 mM DTT, 50 ml 1 M DTT, 20%Glycerol 4 ml 50% Glycerol, add water to 10 ml.

Preparation of Stop Solution:

The stop solution is prepared by mixing the following:

4.2% ammonium molybdate in 4N HCl, 8.4 g/200 ml 4N HCl, 0.045% malachitegreen, 90 mg/200 ml water, then stir 1 part ammonium molybdate with 2parts malachite green for 30 min.

A procedure similar to that described by C. T. Walsh in Biochemistry 33,10646-10651, is used to evaluate the inhibitory activity of testcompounds against MurA, the enzyme which catalyzes the first step ofbacterial cell wall biosynthesis. Experiments are performed by adding asolution of test compound (in a mixture of dimethylsulfoxide and water)and an enzyme solution to a well. After a pre-incubation period of 10minutes at 37° C., Tris/BME buffer and assay buffer are added. A startpoint optical density (OD₀) reading is taken at 340 nm immediatelyfollowing the addition of assay buffer. After incubation for 1 hr at 37°C., the stop solution is added and the color is allowed to develop for30 minutes. An end point OD₁ reading at 660 nM is then taken. The %inhibition at a concentration of 25 μg/ml is calculated for each testcompound using the formula:

${\% \mspace{14mu} {inhibition}} = {100 - {\frac{{OD}_{1} - {{OD}_{0}\mspace{14mu} {for}\mspace{14mu} {test}\mspace{14mu} {compound}}}{{OD}_{1} - {{OD}_{0}\mspace{14mu} {mean}\mspace{14mu} {of}\mspace{14mu} {control}}} \times 100}}$

Using these values, the concentration required to give 50% inhibition(IC₅₀) for each test compound is determined by linear regressionanalysis. The results are shown in Table III.

S. aureus and E. coli Enopyruvyl-UPD-N-acetylglucosamine reductase, MurB

Preparation of Tris/BME Buffer:

Dilute 17.5 uL of aqueous 5 mM BME (2-mercaptoethanol) to 50 mL with 50mM Tris/HCl (pH 8.0).

Preparation of Enzyme Solution:

Dilute aqueous MurB stock solution (0.94 mg/mL) with 200 parts 50 mMTris/2-BME buffer. The final MurB concentration is 4.7 μg/mL.

Synthesis of Substrate for MurB (MurA product EP-UDP-GluNAc):

A mixture of 13 mg UDP-N-acetylglucosamine and 5.5 mgphosphoenolpyruvate are dissolved in 10 mL Tris/BME buffer forming 2 mMconcentrations of each reagent in solution. The solution is incubatedwith 300 μg purified MurA at 37° C. overnight to give approximately70-80% product yield.

Preparation of Assay Buffer:

The assay buffer is prepared in water from reagents with the followingfinal concentrations: 100 mM Tris/HCl (pH 8.0), 200 μM NADPH, 100 μMMurB substrate, 10 μM 2-mercaptoethanol, and 10 μM KCl.

A procedure similar to that described by Dhalla et al., in Biochemistry1995, 34, 5390, is used to evaluate the inhibitory activity of testcompounds against MurB, the enzyme which catalyzes the second step ofbacterial cell wall biosynthesis. Experiments are performed by adding 20μL of a solution of test compound in a mixture of dimethylsulfoxide andwater and 30 μL of enzyme solution to a well. After a pre-incubationperiod of 20 mins. at 23° C., 50 μL of Tris/BME buffer and 100 μL ofassay buffer are added. A start point optical density (OD₀) reading istaken at 340 μM immediately following the addition of assay buffer usinga Molecular Devices Spectra Max 250 with SoftMax software. After a 20min. incubation period at 23° C., an endpoint OD₁ reading is taken at340 μM. Controls are performed using the same procedure and employing 20μL of a blank dimethylsulfonide and solvent mixture in place of the testcompound solution. The % inhibition at concentrations of 10 μg/ml and 25μg/ml are calculated using the formula:

${\% \mspace{14mu} {inhibition}} = {100 - {\frac{{{Sample}\mspace{14mu} {OD}_{1}} - {{Sample}\mspace{14mu} {OD}_{0}}}{{{Control}\mspace{14mu} {OD}_{1}} - {{Control}\mspace{14mu} {OD}_{0}}} \times 100}}$

Using these values, the IC₅₀ for each test compound is determined bylinear regression analysis. The results are shown in Table III.

S. aureus and E. coli Uridine-diphosphate-N-acetylmuramoyl: L-alaninelipase, MurC

Preparation of Buffer:

The buffer is prepared from aqueous reagents with the following finalconcentrations: 83 mM Tris/HCl (pH 8.0), 50 mM MgC₁₂, and 2 mM ATP.

Preparation of Enzyme Solution:

A 1 mg/mL stock solution of MurC is prepared in a buffer consisting of20 mM Tris/HCl (pH 8.5) with 2.5 μM BME. The stock solution is furtherdiluted with the buffer to give a final enzyme concentration of 100μg/mL for the E. coli stock solution and 70 μg/mL for the S. aureusstock solution.

Preparation of Test Compound Solutions:

All test solutions are prepared in DMSO as 10 mg/mL, then diluted with50 mM Tris/HCl (pH 8.5) to 100 μg/m L.

Preparation of Stop Solution:

The stop solution is prepared by stirring 1 part 4.2% ammonium molybdatein 4N HCl with 2 parts 0.045% malachite green for 30 min.

In this evaluation, the inhibitory activity of a test compound againstMurC, the enzyme which catalyzes the third step of bacterial cell wallbiosynthesis is determined. Experiments are performed by adding 2.5 μlbuffer, 2.5 μl 0.5M NH₄SO₂, 5 μl 2 μM L-Ala, 5 μl enzyme solution and6.5 μl test compound solution to each well in a 96-well microplate.After a pre-incubation period of 10 mins. at 23° C., 3.75 μl of a 0.75μM solution of UDP-MurNac is added to each well. Following an incubationperiod of 10 mins. at 37° C., 210 μl stop solution and 50 μl of a 34%w/v sodium citrate solution are added and color is allowed to developfor 10 mins. at 23° C. (Lanzetta et al., Analytical Biochemistry, 1979,95) Optical density readings are taken at 660 nm using a MolecularDevices Spectra Max 250 with Soft Max software. Controls are performedusing the same procedure and omitting the addition of UDP-MurNac. The %inhibition of a concentration of 25 μg/ml is calculated for each testcompound using the formula:

${\% \mspace{14mu} {inhibition}} = {100 - {\frac{{Sample}\mspace{14mu} {OD}}{{mean}\mspace{14mu} {Control}\mspace{14mu} {OD}} \times 100}}$

Using these values the IC₅₀ is determined by linear regression analysis.The results are shown in Table III.

S. aureus and E. coli Uridine-diphosphate-N-acetylmuramoyl-L-alanine:D-glutamate ligase, MurD

Preparation of Buffer:

The buffer is prepared from aqueous reagents with the following finalconcentrations: 83 mM Tris/HCl (pH 8.0), 50 mM MgCl₂, and 2 mM ATP.

Preparation of Enzyme Solution:

A 1 mg/mL stock solution of MurD is prepared in a buffer consisting of20 mM Tris/HCl (pH 8.5) with 2.5 μM BME. The stock solution is furtherdiluted with the buffer to give a final enzyme concentration of 22 μg/mLfor the E. coli stock solution and 11.1 μg/mL for the S. aureus stocksolution.

Preparation of Test Compound Solutions:

All test solutions are prepared in DMSO as 10 mg/mL, then diluted with50 mM Tris/HCl (pH 8.5) to 100 μg/mL.

Preparation of Stop Solution:

The stop solution is prepared by stirring 1 part 4.2% ammonium molybdatein 4N HCl with 2 parts 0.045% malachite green for 30 min.

In this evaluation, the inhibitory activity of a test compound againstMurD, the enzyme which catalyzes the fourth step of bacterial cell wallbiosynthesis is determined. Using essentially the same proceduredescribed hereinabove for evaluating MurC and employing MurD as theenzyme, the % inhibition at 25 μg/ml and the IC₅₀ for each test compoundis determined. The results are shown in Table IV, wherein (E) designatesE. coli and (S) designates S. aureus.

TABLE IV Ex. MurA MurB MurC MurD No. IC₅₀ (μg/mL) IC₅₀ (μg/mL) IC₅₀(μg/mL) IC₅₀ (μg/mL) 4 >25 (E) 10 (E); 10 (S) 7 (E); 16 (S) >25 (E); 24(S) 5 >25 (E) 8 (E); 6 (S) 6 (E) >25 (E) 6 >25 (E) >25 (E); 21 (S) 16(E) >25 (E) 7 >25 (E) 21 (E) 13 (E) >25 (E) 8 >25 (E) 11 (E) 6 (E) >25(E) 9 >25 (E) 16 (E) >25 (E) >25 (E) 10 1 (E) 6 (E) 4 (E); 7 (S) 21 (E);13 (S) 11 1 (E) 6 (E) 4 (E); 5 (S) 21 (E); 11 (S 12 >25 (E) >25 (E) 15(E) >25 (E) 13 0.5 (E) 12 (E) 4 (E); 15 (S) >25 (E); 20 (S) 14 5 (E) >25(E) 13 (E); 22 (S) >25 (E); >25 (S) 15 >25 (E) >25 (E) 17 (E); >25(S) >25 (E); >25 (S) 16 >25 (E) >25 (E) 7 (E); 22 (S) >25 (E); >25 (S)17 >25 (E) >24 (E) 10 (E); >25 (S) >25 (E); >25 (S) 18 6 (S) 6 (E); 5(S) 10 (S) 18 (S) 19 17 (S) 20 (E); 10 (S) 6 (E); 19 (S) >25 (E); 17 (S)20 >25 (S) 3 (E); 3 (S) 11 (E); 15 (S) >25 (E); 19 (S) 21 5 (S) 5 (E); 3(S) 20 (S) 8 (S) 22 9 (S) 6 (E); 6 (S) 12 (S) 17 (S) 23 14 (S) 4 (E); 5(S) 12 (S) 10 (S) 24 7 (S) 4 (E); 2 (S) 12 (S) 11 (S) 25 5 (S) 2 (E); 2(S) 12 (S) 14 (S) 26 4 (S) 3 (E); 2 (S) 6 (S) 9 (S) 27 2 (S) 3 (E); 2(S) >25 (S) 24 (S) 28 10 (S) 3 (E); 3 (S) >25 (S) >25 (S) 29 2 (S) 2(E); 2 (S) 24 (S) 17 (S) 30 3 (S) 2 (E); 2 (S) >25 (S) >25 (S) 31 2 (S)2 (E); 2 (S) >25 (S) 10 (S) 32 10 (S) 6 (E); 3 (S) 12 (S) 9 (S) 33 4 (S)2 (E); 2 (S) >25 (S) >25 (S) 34 22 (S) 6 (S) 21 (S) >25 (S) 35 >25 (S) 6(S) 8 (S) 17 (S) 36 6 (S) 3 (S) 5 (S) 9 (S) 37 >25 (S) 10 (S) 10 (S) 19(S) 38 >25 (S) 8 (S) 7 (S) 6 (S) 39 15 (S) 8 (E); 4 (S) 8 (S) 15 (S) 4014 (S) — 4 (S) 7 (S) 41 >25 (E) >25 (E) 13 (E) >25 (E) 42 20 (E) 10 (E)6 (E); 18 (S) >25 (E); >25 (S) 43 20 (E) 6 (E); 5 (S) 4 (E); 21 (S) >25(E); >25 (S) 44 18 (E) 7 (E) 6 (E) >25 (E) 45 >25 (E) 2 (E) 10 (E) >25(E); >25 (S) 46 >25 (E) >25 (E) 16 (E) >25 (E) 47 >25 (E) 23 (E); 10 (S)11 (E) >25 (E); >25 (S) 48 >25 (E) >25 (E) 13 (E) >25 (E) 49 17 (E) 11(E) 9 (E) >25 (E) 50 16 (E) >25 (E) 9 (E) >25 (E) 51 >25 (E) >25 (E) 9(E); 20 (S) >25 (E); >25 (S) 52 >25 (E) >25 (E) 17 (E); >25 (S) 23 (E);20 (S) 53 >25 (E) 6 (E) 5 (E); 7 (S) 5 (E); 16 (S) 54 >25 (E) 8 (E) 5(E); 11 (S) >25 (E); >25 (S) 55 >25 (E) 4 (E) 11 (E); 22 (S) 24 (E); 15(S) 56 >25 (E) >25 (E) 5 (E); 11 (S) >25 (E); 19 (S) 57 >25 (E) 6 (E) 20(E) 17 (E); 19 (S) 58 >25 (E) >25 (E) 14 (E) >25 (E); >25 (S) 59 17 (E)6 (E) 6 (E) 5 (E); 5 (S) 60 >25 (E) >25 (E) 14 (E) >25 (E); 22 (S)61 >25 (E) >25 (E) 14 (E) >25 (E); 19 (S) 62 7 (E) 15 (E) 5 (E) 5(E); >25 (S) 63 1 (E) 3 (E) 17 (E); 23 (S) 6 (E); >25 (S) 64 6 (E) 3 (E)12 (E) 6 (E); 8 (S) 65 >25 (E) 10 (E) 3 (E) 24 (E); 15 (S) 66 3 (E) 2(E) 3 (E) 21 (E); 5 (S) 67 3 (E) 1 (E) 6 (E); 18 (S) 9 (E); 8 (S) 68 3(E) 3 (E) 9 (E) 11 (E); 11 (S) 69 8 (E) 5 (E) 5 (S) 19 (E); 7 (S) 70 15(S) 7 (E); 5 (S) 5 (E); 8 (S) 17 (E); 9 (S) 71 >25 (S) 10 (E); 10 (S) 11(E); 20 (S) >25 (E); 24 (S) 72 >25 (S) 21 (E); 20 (S) >25(E); >25(S) >25 (E); >25 (S) 73 >25 (S) >25 (E); 12 (S) 19 (E); 23(S) >25 (E); >25 (S) 74 >25 (S) 22 (E); 10 (S) 19 (E); 18 (S) >25(E); >25 (S) 75 >25 (S) >25 (E); 24 (S) 18 (E); 20 (S) >25 (E); >25 (S)76 6 (S) 7 (E); 5 (S) 5 (E); 18 (S) 23 (E); >25 (S) 77 >25 (S) 21 (E);10 (S) 9 (E); 15 (S) >25 (S) 78 >25 (S) 3 (E0; 13 (S) 21 (S) >25 (S) 7914 (S) 6 (E); 1 (S) 24 (S) 14 (S) 80 15 (S) 3 (E); 1 (S) 18 (S) 13 (S)81 >25 (S) 23 (E); 15 (S) 16 (S) >25 (S) 99 4 (E) 6 (E) 4 (E) >25 (E)100 >25 (E) 24 (E) 13 (E); 16 (S) >25 (E); 24 (S) 101 23 (E) >25 (E) 18(E); 23 (S) >25 (E); >25 (S) 102 23 (E) 5 (E); 10 (S) 6 (E); 19 (S) >25(E); 15 (S) 103 >25 (E) 6 (E) 16 (E) >25 (E) 104 >25 (E) 24 (E) 5 (E);19 (S) >25 (E); >25 (S) 105 19 (E) 6 (E) 5 (E); 12 (S) 12 (E); >25 (S)106 9 (E) 12 (E) 9 (E); 12 (S) >25 (E); 16 (S) 107 14 (E) 4 (E) 6(E) >25 (E); 17 (S) 108 19 (E) 10 (E) 6 (E) >25 (E); 15 (S) 109 5 (E) 4(E) 10 (E) >25 (E) 110 7 (E) 5 (E) 9 (E) 19 (E) 111 >25 (E) 11 (E) >25(E) >25 (E) 112 15 (E) 5 (E) 10 (E) >25 (E) 113 4 (E) 3 (E) >25 (E) >25(E) 114 1 (E) 1 (E) 10 (E) 16 (E) 115 5 (E) 5 (E) >25 (E) >25 (E) 116 3(E) 4 (E) >25 (E) >25 (E) 117 10 (E) 7 (E) >25 (E) >25 (E) 118 15 (E) 18(E) 19 (E) >25 (E) 119 1 (E) 1 (E) 2 (E) 6 (E) 120 4 (E) 5 (E) 23 (E) 16(E) 121 9 (E) 7 (E) 9 (E) 25 (E) 122 16 (E) 14 (E) >25 (E) >25 (E) 12321 (E) 3 (E) >25 (E) >25 (E) 124 14 (E) 12 (E) >25 (E) >25 (E) 125 4 (E)5 (E) 1 (E) 20 (E) 126 3 (E) 1 (E) 5 (E) 9 (E) 127 4 (E) 6 (E) >25(E) >25 (E) 128 4 (E) 5 (E) 24 (E) >25 (E) 129 2 (E) 2 (E) 7 (E) 7 (E)130 17 (E) 9 (E) 8 (E) >25 (E) 131 4 (E) 2 (E) 18 (E) 9 (E) 132 3 (E) 3(E) 24 (E) 8 (E) 133 20 (E) 12 (E) 22 (E) 22 (E) 134 5 (E) 4 (E); 2 (S)5 (E); 21 (S) 6 (E); 8 (S) 135 2 (E) 3 (E); 3 (S) 6 (E) 6 (S) 136 1 (S)3 (E); 2 (S) 11 (E); >25 (S) 6 (E); 10 (S) 137 13 (S) 21 (E); 3 (S) 17(E); 23 (S) 18 (S) 138 7 (S) 22 (E); 3 (S) 5 (E); 8 (S) 14 (S) 139 >25(E) 6 (E) 16 (E) >25 (E) 140 11 (S) 4 (E); 3 (S) 8 (S) 20 (S) 141 3 (S)2 (E); 2 (S) >25 (S) 3 (S) 142 >25 (S) 10 (E); 21 (S) >25 (S) >25 (S)143 >25 (S) 7 (E); 4 (S) 5 (S) 10 (S) 144 >25 (S) 20 (E); 10 (S) 10 (S)20 (S)

Example 324 Evaluation of the Minimum Inhibitory Concentration of TestCompounds Against A Variety of Bacterial Strains

In this evaluation the minimal inhibitory concentration (MIC) of testcompounds against Gram positive and Gram negative bacteria is performedusing the microdilution broth method as recommended by the NationalCommittee for Clinical Laboratory Standards (Approved Standards M7-A52000). Mueller-Hinton broth is used for the enterobacteriaceae,staphylococci and enterococci. Streptococci are also tested inMueller-Hinton broth supplemented with 5% horse blood (LHB). Testorganisms include recent clinical isolates that are resistant tomethicillin, penicillin and/or vancomycin. Microtiter plates containing50 μl per well of two-fold serial dilutions of the test compounds in theappropriate broth are inoculated with 50 μl of inoculum to a finalconcentration of 1−5×10⁵ CFU/ml. The MIC is determined after incubationfor 18-22 hours at 35° C. in ambient air. The results are shown in TableV.

TABLE V MIC (μg/mL) Ex. S. aureus S. aureus E. faecalis E. faecalis S.pneumo No. GC 1131 GC 4543 GC 4555 GC 2242 GC 1894 4 16 16 32 8 1 5 8 816 8 0.5 6 32 64 >128 32 8 7 32 64 64 32 2 8 8 8 16 4 0.25 9 32 >128 648 <0.125 10 4 2 8 1 <0.125 11 4 2 8 1 <0.125 12 64 64 >128 64 2 1364 >128 >128 >128 2 14 >128 >128 4 64 64 15 64 64 64 32 0.5 16 64 >12864 64 0.5 17 32 >128 64 32 <0.125 18 4 4 16 8 0.5 19 2 2 8 8 0.5 20 4 416 16 0.5 21 1 0.5 4 2 0.5 22 4 4 16 8 1 23 8 4 8 8 1 24 2 1 4 4 0.5 251 0.5 4 2 0.25 26 2 1 4 2 <0.125 27 0.5 0.5 2 1 0.5 28 1 0.5 4 2 <0.12529 0.5 0.5 2 0.5 <0.125 30 2 1 4 4 0.25 31 0.5 0.25 2 1 0.25 32 2 2 8 40.5 33 0.5 0.5 2 1 0.5 34 32 32 64 64 4 35 8 8 16 8 2 36 4 4 8 4 1 37 1616 32 16 8 38 8 8 32 16 1 39 2 4 8 4 1 40 1 1 2 2 <0.125 41 32 64 64 3232 42 8 8 32 8 8 43 8 8 16 4 1 44 4 8 16 8 1 45 16 4 8 4 2 46 64 32 3264 16 47 16 32 64 32 16 48 32 64 >128 32 8 49 8 8 32 8 0.5 50 8 4 32 8 451 >128 16 32 8 <0.125 52 16 16 8 4 0.5 53 16 16 8 4 0.5 54 8 16 32 4<0.125 55 4 1 4 1 <0.125 56 16 32 32 8 4 57 32 4 8 2 <0.125 58 8 16 >12816 <0.125 59 >128 >128 8 8 32 60 16 16 32 8 8 61 16 16 32 16 862 >128 >128 64 32 64 63 4 0.5 1 0.5 <0.125 64 16 8 8 2 <0.125 65 8 8 164 <0.125 66 2 1 2 0.5 <0.125 67 1 0.5 2 0.5 <0.125 68 2 2 2 1 <0.125 692 1 0.5 0.5 0.25 70 2 1 2 2 0.5 71 8 8 8 4 0.5 72 >128 >128 >128 >128 3273 >128 >128 >128 >128 64 74 64 >128 >128 >128 32 75 64 >128 64 >128 3276 >128 >128 >128 >128 64 77 >128 64 >128 >128 64 78 32 32 64 64 2 79 21 8 4 0.5 80 2 1 8 4 1 81 8 8 32 16 1 99 4 2 16 4 0.25100 >128 >128 >128 >128 64 101 >128 >128 >128 64 64 102 8 4 16 4 1103 >128 64 64 32 0.5 104 16 32 64 32 0.5 105 8 8 8 2 <0.125 106 2 2 10.25 0.25 107 4 2 8 2 0.25 108 2 2 8 2 1 109 2 2 4 1 0.25 110 2 2 4 10.25 111 32 16 16 1 0.25 112 2 4 8 2 0.25 113 1 2 4 1 0.25 114 1 1 2 0.50.25 115 4 4 2 0.25 0.25 116 8 8 4 4 <0.125 117 64 32 32 8 0.5 118 16 1632 16 4 119 2 2 2 2 0.5 120 16 16 8 4 0.5 121 4 2 16 8 0.5 122 16 16 328 1 123 16 16 8 4 0.5 124 32 32 32 16 1 125 2 2 8 4 0.5 126 1 1 4 1 0.25127 4 2 4 2 0.25 128 8 4 8 2 0.25 129 2 2 4 2 0.25 130 4 4 4 8 0.5 13132 16 8 4 0.25 132 16 16 8 4 0.25 133 32 32 16 8 0.5 134 >128 1 8 4 1135 32 1 4 4 1 136 0.25 0.25 1 0.5 0.25 137 8 8 4 4 2 138 4 4 8 4 0.5139 16 16 8 4 1 140 1 1 4 4 1 141 0.5 0.25 1 0.5 <0.125 14264 >128 >128 >128 8 143 8 8 32 4 1 144 16 16 >128 32 2

Example 325 Comparative Evaluation of the Efficacy of a3-Aryl-4-hydroxyfuranone Compound Against Blowfly Larvae

In this evaluation, filter paper discs are treated with an acetonesolution of test compound and allowed to dry. Bovine serum and newlyemerged larvae of blowfly, Lucilia sericata, are added to the treatedfilter paper. Mortality is assessed at 24 h and 48 h. When more than oneevaluation is performed, the data are averaged. The results, at a doserate of 20 ppm, are shown in Table VI, wherein all test compounds arethe Z isomers unless otherwise noted.

TABLE VI

% Mortality R R1 R2 24 h 48 h H 4-biphenyl 1-naphthyl 100 100 H3,5-diCl—C₆H₃ 4-(3-OMe-3′CF₃-biphenyl) 0 0 CH₃ 3-CF₃—C₆H₄ C₆H₅ 0 0 H4-CN—C₆H₄* 4-(4′-CN-biphenyl) 0 0 H 4-CN—C₆H₄** 4-Cl—C₆H₄ 25 100 H4-CN—C₆H₄** 4-CN—C₆H₄ 40 100 H 4-CN—C₆H₄** 4-(4′-Cl-biphenyl) 0 100 H4-Cl—C₆H₄ 4-(4′-CN-biphenyl) 0 0 H 4-Cl—C₆H₄* 4-(4′-CN-biphenyl) 0 100 H4-Cl—C₅H₄** 4-CN—C₆H₄ 0 90 H 4-Cl—C₆H₄** 3-Cl—C₆H₄ 0 0 CH₃ 4-Cl—C₆H₄**4-CN—C₆H₄ 0 0 CO₂t-Bu 4-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 CO₂C₆H₅ 4-Cl—C₆H₄**4-CN—C₆H₄ 0 0 CO₂CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 CH₂CH═CH₂ 4-Cl—C₆H₄**4-CN—C₆H₄ 0 0 H 4-CF₃—C₆H₄** 4-CN—C₆H₄ 100 100 H 4-CF₃—C₆H₄** 4-Cl—C₆H₄100 100 H 4-CF₃—C₆H₄** 4-CF₃—C₆H₄ 100 100 H 4-CF₃—C₆H₄**4-(4′-Cl-biphenyl) 0 65 H 4-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 0 0 H4-CF₃—C₆H₄** 4-F—C₆H₄ 100 100 H 4-F—C₆H₄** 4-CN—C₆H₄ 0 0 H 4-F—C₆H₄**4-Cl—C₆H₄ 0 0 H 4-F—C₆H₄** 4-CF₃—C₆H₄ 0 0 H 4-F—C₆H₄** 4-F—C₆H₄ 0 0 H4-F—C₆H₄ 4-(4′-CN-biphenyl) 0 0 H 4-F—C₆H₄** 4-(4′-Cl-biphenyl) 0 0 H3-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 H 3-Cl—C₆H₄** 4-Cl—C₆H₄ 0 0 H 3-Cl—C₆H₄**4-CF₃—C₆H₄ 60 75 H 3-Cl—C₆H₄** 4-(4′-Cl-biphenyl) 0 0 H 3-Cl—C₆H₄**4-(4′-CN-biphenyl) 0 0 H 3-Cl—C₆H₄** 4-F—C₆H₄ 0 0 H 3-CF₃—C₆H₄**4-CN—C₆H₄ 20 20 H 3-CF₃—C₆H₄** 4-F—C₆H₄ 100 100 H 3-CF₃—C₆H₄**4-CF₃—C₆H₄ 100 100 H 3-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 0 0 H 3-CF₃—C₆H₄**4-(4′-CN-biphenyl) 0 0 H 3-CN—C₆H₄** 4-CN—C₆H₄ 0 0 H 3-CN—C₆H₄**4-Cl—C₆H₄ 0 0 H 3-CN—C₆H₄** 4-CF₃—C₆H₄ 0 0 H 3-CN—C₆H₄**4-(4′-Cl-biphenyl) 0 0 H 3-CN—C₆H₄** 4-(4′-CN-biphenyl) 20 20 H3-CN—C₆H₄** 4-F—C₆H₄ 0 0 H 4-CN—C₆H₄** 4-CF₃—C₆H₄ 100 100 H 4-CN—C₆H₄**3-CF₃—C₆H₄ 0 90 H 4-CN—C₆H₄** 4-(4′-CF₃-biphenyl) 0 25 H 4-CN—C₆H₄**4-F—C₆H₄ 0 0 H 4-Cl—C₆H₄** 4-CF₃—C₆H₄ 100 100 H 4-Cl—C₆H₄** 2-CF₃—C₆H₄10 10 H 4-Cl—C₆H₄** 4-(4′-CF₃-biphenyl) 0 0 H 4-Cl—C₆H₄** 4-F—C₆H₄ 0 0 H4-(4′-Cl-biphenyl)** 4-CF₃—C₆H₄ 0 0 H 4-(4′-Cl-biphenyl)** 4-CN—C₆H₄ 0 0H 4-(4′-Cl-biphenyl)** 4-Cl—C₆H₄ 0 0 H C₆H₅ 3-CF₃—C₆H₄ 0 0 H 4-Cl—C₆H₄4-OMe—C₆H₄ 0 0 H 3-CH₂OH—C₆H₄ 1-naphthyl 0 0 H 3,5-diCl—C₆H₃3-F-4-[1-(4-CO₂C₂H₅- 0 0 piperazinyl)]-C₆H₃ H 3,5-diCl—C₆H₃3-Cl-4-{1-[4-(2-Cl—C₆H₄)- 0 0 piperazinyl]}-C₆H₃ H 4-CN—C₆H₄4-(4′-CN-biphenyl) 0 0 H 3-CH₂OH—C₆H₄ 4-(3′-CH₂OH-biphenyl) 0 0 H3,5-diCl—C₆H₃ 4-(3′,5′-diCl-biphenyl) 0 0 H 4-Cl—C₆H₄ 4-(4′-Cl-biphenyl)0 0 H 4-(4′-t-Bu- 4-biphenyl 0 0 biphenyl) H 4-(biphenyl) 4-CF₃—C₆H₄ 0 0H 3-CF₃—C₆H₄ 4-(3′-CF₃-biphenyl) 0 0 H 3-CF₃—C₆H₄ 4-(3-F-biphenyl) 0 0 H2-CH₂OH—C₆H₄ 4-(2′-CH₂OH-biphenyl) 0 0 H 3-N(COCH₃)C₆H₄4-[3′-N(COCH₃)-biphenyl] 0 0 *E isomer **Mixture of Z and E isomers

Example 326 Evaluation of the Efficacy of a 3-Aryl-4-HydroxyfuranoneAgainst Nematodes

In this evaluation, cultures of C. elegans are maintained on E. colilawns on Nematode Growth Agar at 20° C. New cultures are establishedtwice a week. Nematodes for testing are rinsed from plates using M9Buffer. Test compounds are dissolved in DMSO to give a concentration of10 mg/mL. One μL of this solution is added to each well of a 96 wellplate. A mixture of C. elegans in M9 Buffer (100 μL) is added to eachwell, such that approximately 50 worms of mixed stages (L1, L2, L3, L4and adults) are present in each well at a final concentration of 100ppm, 150 ppm or 200 μM of test compound. Concentration of test compoundmay be varied by gradient dilution of the stock DMSO solution.Observations are made under a dissecting microscope at 4 h and 24 hpostimmersion. A rating is based on the motility of the larvae andadults, using the rating system shown below. The results are shown inTable VII, wherein all test compounds are the Z isomer, unless otherwisenoted.

TABLE VII Rating Description 0 no effect 7 reduced movement in 24 h 8dead in 24 h 9 dead in 4 h

R R1 R2 Dose Rating H 4-biphenyl 4-CF₃—C₆H₄ 150 ppm 9 H 3-CF₃—C₆H₄4-(3′-CF₃- 150 ppm 8 biphenyl) H 4-(3-F-biphenyl) 3-CF₃—C₆H₄ 150 ppm 9 H2-CH₂OH—C₆H₄ 4-(2′-CH₂OH- 150 ppm 0 biphenyl) H 3-N(COCH₃)—C₆H₄ 4-[3′-150 ppm 0 N(COCH₃)biphenyl] H 4-CN—C₆H₄ 4-(4′-CN-biphenyl) 150 ppm 8 H3-CH₂OH—C₆H₄ 4-(3′-CH₂OH- 150 ppm 0 biphenyl) H 3,5-diCl—C₆H₃4-(3′,5′-diCl- 150 ppm 7 biphenyl) H 4-Cl—C₆H₄ 4-(4′-Cl-biphenyl) 150ppm 9 H 4(4′-t-bu-biphenyl) 4-biphenyl 150 ppm 0 H 4-biphenyl 4-biphenyl150 ppm 9 H 1-naphthyl 4-biphenyl 150 ppm 9 H 4-CH₃C₆H₄ 4-(4′-CH₃- 150ppm 0 biphenyl) H 2-F—C₆H₄ 4-(2′-F-biphenyl) 150 ppm 8 H 3-CN—C₆H₄4-(3′-CN-biphenyl) 150 ppm 0 H 2-CH₃—C₆H₄ 4-(2′-CH₃- 150 ppm 8 biphenyl)H 3,5-diCF₃—C₆H₃ 4-(3′,5′-diCF₃- 150 ppm 0 biphenyl) H 2,4-diCl—C₆H₃4-biphenyl 150 ppm 9 H 3,4-diCl—C₆H₃ 4-biphenyl 150 ppm 9 H3,5-diCl—C₆H₃ 4-biphenyl 150 ppm 9 H 3-Cl—C₆H₄ 4-biphenyl 150 ppm 9 H3,5-diCF₃—C₆H₃ 4-biphenyl 150 ppm 9 H 2-CF₃—C₆H₄ 4-biphenyl 150 ppm 8 H3,5-diCl—C₆H₃ 4-(3,2′-diOCH₃- 150 ppm 0 biphenyl) H 3-Cl—C₆H₄4-(3-OCH₃-2′-Cl- 150 ppm 8 biphenyl) H 3,5-diCl—C₆H₃ 4-(3-OCH₃-2′-Cl-150 ppm 7 biphenyl) H 3-Cl—C₆H₄ 4-(3-OCH₃-2′-CH₃ 150 ppm 7 biphenyl) H3-Cl—C₆H₄ 4-(3-CH₃-2′-OCH₃- 150 ppm 7 biphenyl) H 3-5-diCl—C₆H₃4-(3-CH₃-2′-OCH₃O 150 ppm 0 H 3-5-diCl—C₆H₃ 4-(3-OCH₃-2′-CH₃- 150 ppm 9biphenyl) H 3-Cl—C₆H₄ 4-(3-CH₃-2′-CF₃- 150 ppm 9 biphenyl) H3-5-diCl—C₆H₃ 4-(3-CH₃-2′-CF₃- 150 ppm 0 biphenyl) H 3-Cl—C₆H₄4-(3,2′-diCH₃- 150 ppm 9 biphenyl) H 3,5-diCl—C₆H₃ 4-(3-CH₃-2′-Cl- 150ppm 7 biphenyl) H 3-Cl—C₆H₄ 4-(3-CH₃-2′-Cl- 150 ppm 9 biphenyl) H3,5-diCl—C₆H₃ 4-(3,2′-diCH₃- 150 ppm 0 biphenyl) H 3,5-diCl—C₆H₃4-(3-OCH₃-2′-CF₃- 150 ppm 0 biphenyl) H 3-Cl—C₆H₄ 4-(3-OCH₃-2′-CF₃- 150ppm 9 biphenyl) H 3,5-diCl—C₆H₃ 4-(3-CH₃-2′- 150 ppm 8 CH₃SO₃- biphenyl)H 4-OCH₃—C₆H₄ 4-biphenyl 150 ppm 9 H 3-CF₃—C₆H₄ C₆H₅ 150 ppm 8 H4-Cl—C₆H₄ 3-CF₃—C₆H₄ 150 ppm 9 H C₆H₅ 3-CF₃—C₆H₄ 150 ppm 0 H 2-naphthyl3-CF₃—C₆H₄ 150 ppm 9 H 2-naphthyl 1-naphthyl 150 ppm 9 H 4-biphenyl4-Cl—C₆H₄ 150 ppm 9 H 4-Cl—C₆H₄ 4-Cl—C₆H₄ 150 ppm 9 H 4-Cl—C₆H₄1-naphthyl 150 ppm 9 H 3-CF₃—C₆H₄ 3-CF₃—C₆H₄ 150 ppm 9 H 4-OCH₃—C₆H₄2-naphthyl 150 ppm 0 H 4-OCH₃—C₆H₄ 4-OCH₃—C₆H₄ 150 ppm 0 H 4-Cl—C₆H₄4-OCH₃—C₆H₄ 150 ppm 0 H 4-OCH₃—C₆H₄ 4-Cl—C₆H₄ 150 ppm 0 H 1-naphthyl4-Cl—C₆H₄ 150 ppm 0 H 3-CF₃—C₆H₄ 2-naphthyl 150 ppm 9 H 1-naphthyl1-naphthyl 150 ppm 0 H 1-naphthyl 3-CF₃—C₆H₄ 150 ppm 0 H 3-CF₃—C₆H₄4-OCH₃—C₆H₄ 150 ppm 9 H 4-biphenyl 2-CF₃—C₆H₄ 150 ppm 9 H 2-naphthyl2-naphthyl 150 ppm 9 H 4-biphenyl 2-naphthyl 150 ppm 0 H 4-Cl—C₆H₄2-naphthyl 150 ppm 9 H 1-naphthyl 2-naphthyl 150 ppm 9 H4-(3-F-biphenyl) 2-CF₃—C₆H₄ 150 ppm 9 H 4-COCH₃—C₆H₄ 2-CF₃—C₆H₄ 150 ppm0 H 4-CN—C₆H₄ 2-CF₃—C₆H₄ 150 ppm 7 H 4-F—C₆H₄ 2-CF₃—C₆H₄ 150 ppm 0 H3-biphenyl 3-CF₃—C₆H₄ 150 ppm 0 H 3,5-diCl—C₆H₃ 1-naphthyl 150 ppm 9 H4-CF₃—C₆H₄ 1-naphthyl 150 ppm 9 H 3-COCH₃—C₆H₄ 1-naphthyl 150 ppm 8 H4-(CH₃C═NOH)—C₆H₄ 1-naphthyl 150 ppm 7 H 4-CO₂CH₃—C₆H₄ 1-naphthyl 150ppm 9 H 3,4-diCl—C₆H₃ 4-(3′,4′-diCl- 150 ppm 9 biphenyl) H 3-CHO—C₆H₄1-naphthyl 150 ppm 0 H 3-CH₂OH—C₆H₄ 1-naphthyl 150 ppm 0 H3-(C═NOH)—C₆H₄ 1-naphthyl 150 ppm 0 H 4-(3-F-biphenyl) 4-Cl—C₆H₄ 150 ppm9 H 4-Cl—C₆H₄ 2-(4′-Cl-biphenyl) 150 ppm 0 H 4-(3-F-biphenyl)3,5-diCl—C₆H₃ 150 ppm 9 H 3-Cl—C₆H₄ 2-(3′-Cl-biphenyl) 150 ppm 0 H3-F-4-(1-morpho- 2-Cl-5-CF₃—C₆H₃ 150 ppm 0 lino)-C₆H₄ H 4-Cl—C₆H₄ 1-[(4-150 ppm 0 dimethylamino)- naphthyl] H 3,5-diClC₆H₃ 1-[(4- 150 ppm 0dimethylamino)- naphthyl] H 4-CF₃—C₆H₄ 1-[(4- 150 ppm 0 dimethylamino)-naphthyl] H 3-Cl—C₆H₄ 3-F-4-[1-(4- 150 ppm 7 CO₂C₂H₅- piperazinyl)]-C₆H₃H 4-CN—C₆H₄** 4-(4′-Cl-biphenyl) 150 ppm 9 H 4-Cl—C₆H₄4-(4′-CN-biphenyl) 150 ppm 9 H 4-Cl—C₆H₄* 4-(4′-CN-biphenyl) 150 ppm 9 H4-Cl—C₆H₄** 4-CN—C₆H₄ 150 ppm 9 H 4-Cl—C₆H₄** 3-Cl—C₆H₄ 150 ppm 9 H3-CF₃—C₆H₄ 4-Cl—C₆H₄ 100 ppm 9 CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 0CO₂t-Bu 4-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 CO₂C₆H₅ 4-Cl—C₆H₄** 4-CN—C₆H₄100 ppm 9 CO₂CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 CH₂CH═CH₂ 4-Cl—C₆H₄**4-CN—C₆H₄ 100 ppm 0 H 4-CF₃—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 4-CF₃—C₆H₄**4-Cl—C₆H₄ 100 ppm 9 H 4-CF₃—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 4-CF₃—C₆H₄**4-(4′-Cl-biphenyl) 100 ppm 9 H 4-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 100 ppm 9H 4-CF₃—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 4-F—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H4-F—C₆H₄** 4-Cl—C₆H₄ 100 ppm 9 H 4-F—C₆H₄* 4-CF₃—C₆H₄ 100 ppm 9 H4-F—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 4-F—C₆H₄ 4-(4′-CN-biphenyl) 100 ppm 9 H4-F—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 3-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm9 H 3-Cl—C₆H₄** 4-Cl—C₆H₄ 100 ppm 9 H 3-Cl—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H3-Cl—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 3-Cl—C₆H₄**4-(4′-CN-bipehnyl) 100 ppm 9 H 3-Cl—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H3-CF₃—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 3-CF₃—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H3-CF₃—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 3-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 100ppm 9 H 3-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 100 ppm 9 H 3-CN—C₆H₄**4-CN—C₆H₄ 100 ppm 9 H 3-CN—C₆H₄** 4-Cl—C₆H₄ 100 ppm 9 H 3-CN—C₆H₄**4-CF₃—C₆H₄ 100 ppm 9 H 3-CN—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H3-CN—C₆H₄** 4-(4′-CN-biphenyl) 100 ppm 9 H 3-CN—C₆H₄** 4-F—C₆H₄ 100 ppm7 H 4-CN—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 3-CF₃—C₆H₄ 100 ppm 9H 4-CN—C₆H₄** 4-(4′-CF₃- 100 ppm 9 biphenyl) H 4-CN—C₆H₄** 4-F—C₆H₄ 100ppm 9 H 4-Cl—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 2-CF₃—C₆H₄ 100ppm 9 H 4-Cl—C₆H₄** 4-(4′-CF₃-biphenyl) 100 ppm 9 H 4-Cl—C₆H₄** 4-F—C₆H₄100 ppm 9 H 4-(4′-Cl-biphenyl)** 4-CF₃—C₆H₄ 100 ppm 9 H4-(4′-Cl-biphenyl)** 4-CN—C₆H₄ 100 ppm 9 H 4-(4′-Cl-biphenyl)**4-Cl—C₆H₄ 100 ppm 9 H 4-(4′-CN-biphenyl)** 4-CF₃—C₆H₄ 100 ppm 9 H4-(4′-CN-biphenyl)** 4-CN—C₆H₄ 100 ppm 9 H 4-(4′-CN-biphenyl)**4-Cl—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 3,4-diCl—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄**2,4-diCl—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 3-F-4-CF₃—C₆H₄ 100 ppm 9 H4-CN—C₆H₄** 3,4-diCl—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 2,4-diCl—C₆H₄ 100 ppm9 H 4-CN—C₆H₄** 3-F-4-CF₃—C₆H₄ 100 ppm 9 CH₃ 3-CF₃—C₆H₄ 3-CF₃—C₆H₄ 150ppm 0 CH₃ 4-OCH₃—C₆H₄ C₆H₅ 150 ppm 0 CH₃ 4-OCH₃—C₆H₄ 3-CF₃—C₆H₄ 150 ppm0 CH₃ 3-CF₃—C₆H₄ C₆H₅ 150 ppm 0 CH₃ 4-Cl—C₆H₄ C₆H₅ 150 ppm 0 CH₃ C₆H₅3-CF₃—C₆H₄ 150 ppm 0 H 4-biphenyl 3-F-5-CF₃—C₆H₃ 200 μM 9 H4-(3-F-biphenyl) 3-F-5-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nBu-biphenyl)3-F-5-CF₃—C₆H₃ 200 μM 9 H 3-biphenyl 3-F-5-CF₃—C₆H₃ 200 μM 9 H4-(2-F-biphenyl) 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nPr-biphenyl)2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nBu-biphenyl) 2-Cl-3-CF₃—C₆H₃ 200 μM 9H 4-(4′-nPr-biphenyl) 2-F-5-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nBu-biphenyl)2-F-5-CF₃—C₆H₃ 200 μM 0 H 3-biphenyl 2-F-5-CF₃—C₆H₃ 200 μM 9 H4-(4′-OC₂H₅-biphenyl) 2-F-5-CF₃—C₆H₃ 200 μM 9 H 4-biphenyl2-Cl-5-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nPr-biphenyl) 2-Cl-5-CF₃—C₆H₃ 200 μM 0H 4-(4′-tBu-biphenyl) 3-CF₃—C₆H₄ 200 μM 0 H 3-isopropyl-C₆H₄2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 4-(C₂H₅)—C₆H₄ 2-Cl-5-CF₃—C₆H₃ 200 μM 9 H4-CH₃—C₆H₄ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 2,3-di-CH₃—C₆H₃ 2-Cl-5-CF₃—C₆H₃200 μM 0 H 3,4-di-CH₃—C₆H₃ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 3,5-di-CH₃—C₆H₃2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 2,5-di-CH₃—C₆H₃ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H4-isopropyl-C₆H₄ 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-CH₃—C₆H₄ 2-Cl-3-CF₃—C₆H₃200 μM 9 H 3,4-di-CH₃—C₆H₃ 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-biphenyl3-CF₃—C₆H₄ 200 μM 9 H 3,5-diCl—C₆H₃ 3-F-4-[1-(4- 150 ppm 0 CO₂C₂H₅-piperazinyl)]-C₆H₃ H 3-Cl—C₆H₄ 1-(4-OCH₃- 150 ppm 9 naphthyl) H3,5-diCl—C₆H₃ 1-(4-OCH₃- 150 ppm 0 naphthyl) H 3-Cl—C₆H₄1-[4-(N-morpholino)- 150 ppm 0 naphthyl)] H 3,5-diCl—C₆H₃1-[4-(N-morpholino)- 150 ppm 0 naphthyl)] H 3,5-diCl—C₆H₃3-(benzyloxy)-C₆H₄ 150 ppm 0 H 3,5-diCl—C₆H₃ 2-(benzyloxy)-C₆H₄ 150 ppm0 H 3,5-diCl—C₆H₃ 3-Cl-4-{1-[4-(2-Cl—C₆H₄)- 150 ppm 0 piperazinyl)}-C₆H₃H 3,5-diCl—C₆H₃ 3- 150 ppm 0 (CONHCH₂CONHCH₂—CO₂C₂H₅)—C₆H₄ H3,5-diCl—C₆H₃ 3- 150 ppm 0 (CONHCH₂CONHCH₂—CO2C₂H₅)—C₆H₄ H 3,5-diCl—C₆H₃4-(3-CH₃-2-COCH₃- 150 ppm 0 biphenyl) H 4-CN—C₆H₄* 4-(4′-CN-biphenyl)150 ppm 9 H 4-CN—C₆H₄** 4-Cl—C₆H₄ 150 ppm 9 H 4-CN—C₆H₄** 4-CN—C₆H₄ 150ppm 9 H 4-F—C₆₄** 4-OCF₃—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 4-OCF₃—C₆H₄ 100ppm 9 H 4-CN—C₆H₄** 4-OCHF₂—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 4-OCF₂CHF₂—C₆H₄100 ppm 9 H 4-CN—C₆H₄** 5-chlorothiophen-2- 100 ppm 9 yl H 4-CN—C₆H₄**2,2difluoro-1,3- 100 ppm 9 dioxol- C₆H₃-5-yl H 4-OCF₃—C₆H₄**3,5-diCl—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 3,4-diF—C₆H₃ 100 ppm 9 H4-OCF₃—C₆H₄** 4-n-propoxy-C₆H₄ 100 ppm 0 H 4-OCF₃—C₆H₄** 3,4-diCl—C₆H₃100 ppm 9 H 4-OCF₃—C₆H₄** 3-F-4-CF₃—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄**5-chlorothiophen-2- 100 ppm 9 yl H 4-OCF₃—C₆H₄** thiophen-2-yl 100 ppm 0H 4-OCF₃—C₆H₄** 4-phenoxy-C₆H₄ 100 ppm 0 H 4-OCF₃—C₆H₄** pyridine-3-yl100 ppm 0 H 4-OCF₃—C₆H₄** 4-OCF₃—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-F—C₆H₄100 ppm 9 H 4-OCF₃—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-Cl—C₆H₄100 ppm 9 H 4-OCF₃—C₆H₄** 4-OCHF₂—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄**2-F-5-CF₃—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H4-OCF₃—C₆H₄** 3-F-5-CF₃—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 2-F-4-CF₃—C₆H₃100 ppm 9 H 4-OCF₃—C₆H₄** 4-OCF₂CHF₂—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄**2,2difluoro-1,3- 100 ppm 9 dioxol- C₆H₃-5-yl H 4-OCF₃—C₆H₄**pyridine-4-yl 100 ppm 0 H 4-OCF₃—C₆H₄** pyridine-2-yl 100 ppm 0 H4-OCF₃—C₆ ₄** 3-Br-pyridine-2-yl 100 ppm 0 H 4-OCF₃—C₆H₄**4-(4-F-phenyl)- 100 ppm 9 pyridin-3-yl H 4-OCF₃—C₆H₄**4-(thiophen-2-yl)- 100 ppm 9 pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(4-OCF₃- 100ppm 9 phenyl)- pyridin3-yl H 4-OCF₃—C₆H₄** 4-(5-Cl-thiophen-2- 100 ppm 9yl)- pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(4-Cl-phenyl)-pyridin- 100 ppm 93-yl H 4-OCF₃—C₆H₄** 4-(3-Cl-phenyl)-pyridin- 100 ppm 9 3-yl H4-OCF₃—C₆H₄** 4-Br-pyridine-3-yl 100 ppm 9 H 4-OCF₃—C₆H₄**3-Cl-pyridine-4-yl 100 ppm 9 H 4-OCF₃—C₆H₄** 4-cyclopropylmethoxy- 100ppm 0 C₆H₄ H 4-OCF₃—C₆H₄** 4-(5-Cl-thiophen-2-yl)- 100 ppm 9 C₆H₄ H4-OCF₃—C₆H₄** 2-methyl-1H- 100 ppm 0 imidazol-4-yl H 4-OCF₃—C₆H₄**5-chloro-1,3- 100 ppm 0 dimethyl- 1H-pyrazol-4-yl H 4-OCF₃—C₆H₄**5-methyl-1-o-tolyl- 100 ppm 0 1H- pyrazol-4-yl H 4-OCF₃—C₆H₄**2-phenyl-1H- 100 ppm 0 imdiazol-4-yl H 4-OCF₃—C₆H₄** 2-Cl-pyridine-3-yl100 ppm 9 H 4-OCF₃—C₆H₄** 4-chloro-1-methyl- 100 ppm 0 1H- pyrazol-3-ylH 4-OCF₃—C₆H₄** 5-(4-F-3-CF₃- 100 ppm 9 phenyl)- furan-2-yl H4-OCF₃—C₆H₄** 5-chloro-1-methyl- 100 ppm 0 3- trifluoromethyl-1H-imidazol-3-yl H 4-OCF₃—C₆H₄** 5-bromo-1-methyl- 100 ppm 0 1H-imidazol-3-yl H 4-OCF₃—C₆H₄** 1-(4-methoxyphenyl)- 100 ppm 0 5-methyl-1H-pyrazol-4- yl H 4-OCF₃—C₆H₄** 1-(4-fluorophenyl)-5- 100 ppm 0methyl-1H-pyrazol-4- yl H 4-OCF₃—C₆H₄** 1-(phenyl)-5-methyl- 100 ppm 01H- pyraozl-4-yl H 4-OCF₃—C₆H₄** 2-methanesulfanyl- 100 ppm 9nicotinonitrile H 4-OCF₃—C₆H₄** 5-bromo-furan-2-yl 100 ppm 9 H4-OCF₃—C₆H₄** 6-phenoxy-pyridin- 100 ppm 9 3-yl H 4-OCF₃—C₆H₄**4-(1,2,4-triazol-1- 100 ppm 9 yl)- C₆H₄ H 4-OCF₃—C₆H₄**5-(pyridine-2-yl)- 100 ppm 9 thiphen-2-yl H 4-OCF₃—C₆H₄**5-(6-morpholin-4- 100 ppm 0 yl)- pyridin-3-yl H 4-OCF₃—C₆H₄**4-(4-methyl- 100 ppm 0 piperazin-1- yl)-C₆H₄ H 4-OCF₃—C₆H₄**4-(thiophen-2-yl)- 100 ppm 9 C₆H₄ H 4-OCF₃—C₆H₄** 4-(pyrrol-1-yl)- 100ppm 9 C₆H₄ H 4-OCF₃—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 4-OCF₃—C₆H₄**4-(4′-CN-biphenyl) 100 ppm 9 H 4-OCF₃—C₆H₄** 2,5-dimethyl-2H- 100 ppm 0pyrazol-3-yl H thiophen-2-yl 4-CN—C₆H₄ 100 ppm 0 H thiophen-2-yl4-Cl—C₆H₄ 100 ppm 7 H thiophen-2-yl 4-CF₃—C₆H₄ 100 ppm 7 H5-chlorothiophen-2-yl 4-Cl—C₆H₄ 100 ppm 9 H 5-chlorothiophen-2-yl4-CN—C₆H₄ 100 ppm 9 H 5-chlorohtiophen-2-yl 4-CF₃—C₆H₄ 100 ppm 9 H5-chlorothiophen-2-yl 4-OCF₃—C₆H₄ 100 ppm 9 H 5-chlorothiophen-2-yl4-OCHF₂—C₆H₄ 100 ppm 9 H 5-chlorothiophen-2-yl 3,4-diCl—C₆H₃ 100 ppm 9 H5-chlorothiophen-2-yl 3,4-diF—C₆H₃ 100 ppm 9 H 5-chlorothiophen-2-yl4-F-3-CF₃—C₆H₃ 100 ppm 9 H 5-chlorothiophen-2-yl 4-F—C₆H₄ 100 ppm 9 H5-chlorothiophen-2-yl 4-cyclopropylmethoxy- 100 ppm 9 C₆H₄ H5-chlorothiophen-2-yl 5-chlorothiophen-2- 100 ppm 9 yl H 4-Cl—C₆H₄**4-cyclopropylmethoxy- 100 ppm 7 C₆H₄ H 4-Cl—C₆H₄** 4-SCF₃—C₆H₄ 100 ppm 9*E isomer **Mixture of Z and E isomers

Example 327 In Vivo Evaluation of the Efficacy of Test Compounds AgainstT. colubriformis

In this evaluation, gerbils are infected with Trichostrongyluscolumbriformis infective larvae at a concentration of approximately 800L₃/mL. Larvae for gerbil infections are cultured from feces from sheeppreviously infected with T. colubriformis. One week post infection, testcompounds are administered by gavage as a single oral dose of 50 mg/kgof body weight. For each group of 3 gerbils, 10 mg of test compound aredissolved in 2 mL of PEG 400:DMSO (1:2 v/v) and each animal isadministered the test solution at a rate of 0.1 mL/10 g of body weight.Treatments are randomly allocated to groups of 3 infected gerbils each;35 groups are treated with test compounds; 4 groups are untreated(administered vehicle only) as a negative control; and one group istreated with a known endectoside, NEMADECTIN as a positive control. Allanimals are observed daily for morbidity and mortality. Four dayspost-treatment, all animals are weighed and necropsied. Worm counts areconducted with the use of stereoscopes and counters. The results arerecorded as % mortality as compared to that of the negative control forthe worms. Toxicity is indicated for those groups having one or moreanimals expired or demonstrating significant weight loss as compared tothe negative control. The data are shown in Table VIII, wherein all testcompounds are the Z isomer, unless otherwise noted.

TABLE VIII

R R1 R2 Mortality Toxicity H 4-biphenyl 4-CF₃—C₆H₄ 0.00 − H4-(3-F-biphenyl) 3-CF₃—C₆H₄ 20.60 − H 4-CN—C₆H₄ 4-(4′CN-biphenyl)88.60 + H 4-Cl—C₆H₄ 4-(4′-Cl-biphenyl) 61.33 + H 4-Cl—C₆H₄ 4-biphenyl33.10 + H 1-naphthyl 4-biphenyl 18.50 − H 2-F—C₆H₄ 4-(2′F-biphenyl)12.40 − H 2-CH₃—C₆H₄ 4-(2′-CH₃-biphenyl) 21.30 − H 2,4-diCl—C₆H₃4-biphenyl 24.50 − H 3,5-diCl—C₆H₃ 4-biphenyl 52.60 + H 3-Cl—C₆H₄4-biphenyl 19.40 − H 3,5-diCF₃—C₆H₃ 4-biphenyl 60.80 + H 2-CF₃—C₆H₄4-biphenyl 20.20 − H 3-Cl—C₆H₄ 4-(3-OCH₃-2′-Cl-biphenyl) 0.00 − H3-Cl—C₆H₄ 4-(3-CH₃-2′-OCH₃-biphenyl 0.00 − H 3-Cl—C₆H₄4-(3-CH₃-2′-CF₃-biphenyl 11.20 − H 3-Cl—C₆H₄ 4-(3,2′-diCH₃-biphenyl)10.80 − H 3-Cl—C₆H₄ 4-(3-CH₃-2′-Cl-biphenyl) 16.90 − H 3-Cl—C₆H₄4-(3-OCH₃-2′-CF₃-biphenyl) 29.50 + H 4-OCH₃—C₆H₄ 4-biphenyl 44.90 − H4-(3-F-biphenyl) 4-(3-F-biphenyl) 17.00 − H 3-CF₃—C₆H₄ 2-naphthyl 35.20− H 2-naphthyl 1-naphthyl 36.10 − H 4-Cl—C₆H₄ 4-Cl—C₆H₄ 79.78 + H4-Cl—C₆H₄ 4-Cl—C₆H₄ 79.78 + H 3-CF₃—C₆H₄ 3-CF₃—C₆H₄ 10.10 − H 4-Cl—C₆H₄4-OCH₃—C₆H₄ 7.10 — H 3-CF₃—C₆H₄ 4-OCH₃—C₆H₄ 3.10 − H 4-biphenyl2-CF₃—C₆H₄ 23.90 − H 2-naphthyl 2-naphthyl 13.80 − H 4-Cl—C₆H₄2-naphthyl 52.80 − H 1-naphthyl 2-naphthyl 28.90 − H 4-(3-F-biphenyl)2-CF₃—C₆H₄ 51.60 − H 4-CN—C₆H₄ 2-CF₃—C₆H₄ 69.78 − H 3,5-diCl—C₆H₃1-naphthyl 0.00 − H 3-COCH₃—C₆H₄ 1-naphthyl 10.70 — H 3,4-diCl—C₆H₃4-(3′,4′-diCl-biphenyl) 22.00 − H 4-(3-F-biphenyl) 4-Cl—C₆H₄ 22.00 − H4-CN—C₆H₄* 4-(4′-CN-biphenyl) 88.07 − H 4-CN—C₆H₄ 4-Cl—C₆H₄ 90.20 + H4-CN—C₆H₄ 4-CN—C₆H₄ 62.43 + H 4-CN—C₆H₄ 4-(4′-Cl-biphenyl) 64.33 + H4-Cl—C₆H₄ 4-(4′-CN-biphenyl) 48.90 + H 4-Cl—C₆H₄* 4-(4′-CN-biphenyl)23.80 − H 4-Cl—C₆H₄ 4-CN—C₆H₄ 84.54 + H 4-Cl—C₆H₄ 3-Cl—C₆H₄ 25.40 − H3,4-diCl—C₆H₃ 4-biphenyl 23.00 − H 3,5-diCl—C₆H₃4-(3-OCH₃-2′-Cl-biphenyl) 41.00 − H 3-biphenyl 3-F-5-CF₃—C₆H₄ 0.00 − H3-biphenyl 2-F-5-CF₃—C₆H₄ 38.40 − H 4-biphenyl 2-Cl-5-CF₃—C₆H₄ 38.40 − H4-(C₂H₅)—C₆H₄ 2-Cl-5-CF₃—C₆H₄ 39.00 − H 3,4-diCH₃—C₆H₃ 2-Cl-3-CF₃—C₆H₄36.50 − H 2-CF₃—C₆H₄ C₆H₅ 34.60 − H 4-biphenyl 4-Cl—C₆H₄ 44.70 − H4-Cl—C₆H₄ 1-naphthyl 0.00 − H 3-CF₃—C₆H₄ 4-Cl—C₆H₄ 21.60 − CH₃4-Cl—C₆H₄** 4-CN—C₆H₄ 0.00 − CO₂tBu 4-Cl—C₆H₄** 4-CN—C₆H₄ 0.00 − CO₂C₆H₅4-Cl—C₆H₄** 4-CN—C₆H₄ 0.00 − CO₂CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 96.90 −CH₂CH═CH₂ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0.00 — H 4-CF₃—C₆H₄ 4-(4′-CN-biphenyl)91.50 − H 4-CF₃—C₆H₄** 4-F—C₆H₄ 95.80 + H 4-F—C₆H₄** 4-CN—C₆H₄ 14.70 − H4-F—C₆H₄** 4-Cl-C₆H₄ 0.00 − H 4-F—C₆H₄** 4-CF₃—C₆H₄ 25.60 − H 4-F—C₆H₄**4-F—C₆H₄ 0.00 − H 4-F—C₆H₄ 4-(4′-CN-biphenyl) 31.80 − H 4-F—C₆H₄**4-(4′-Cl-biphenyl) 1.60 − H 3-Cl—C₆H₄** 4-CN—C₆H₄ 43.70 − H 3-Cl—C₆H₄**4-Cl—C₆H₄ 18.80 − H 3-Cl—C₆H₄** 4-CF₃—C₆H₄ 57.90 − H 3-Cl—C₆H₄**4-(4′-Cl-biphenyl) 37.60 − H 3-Cl—C₆H₄** 4-(4′-CN-biphenyl) 32.00 − H3-Cl—C₆H₄** 4-F—C₆H₄ 3.00 − H 3-CF₃—C₆H₄** 4-CN—C₆H₄ 0.00 − H3-CF₃—C₆H₄** 4-F—C₆H₄ 36.40 − H 3-CF₃—C₆H₄** 4-CF₃—C₆H₄ 0.00 − H3-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 31.30 − H 3-CF₃—C₆H₄**4-(4′-CN-biphenyl) 47.50 − H 3-CN—C₆H₄** 4-CN—C₆H₄ 25.50 − H 3-CN—C₆H₄**4-Cl—C₆H₄ 0.00 − H 3-CN—C₆H₄** 4-CF₃—C₆H₄ 0.00 − H 3-CN—C₆H₄**4-(4′-Cl-biphenyl) 0.00 — H 3-CN—C₆H₄** 4-(4′-CN-biphenyl) 30.30 − H3-CN—C₆H₄** 4-F—C₆H₄ 0.00 − H 4-CN—C₆H₄** 3-CF₃—C₆H₄ 50.00 − H4-CN—C₆H₄** 4-F—C₆H₄ 82.10 − H 4-Cl—C₆H₄** 4-(4′_CF₃-biphenyl) 0.00 − H4-Cl—C₆H₄** 4-F—C₆H₄ 72.60 + H 4-(4′-Cl-biphenyl)** 4-CF₃—C₆H₄ 21.30 − H4-(4′-Cl-biphenyl)** 4-CN—C₆H₄ 0.00 − H 4-(4′-Cl-biphenyl)** 4-Cl—C₆H₄0.00 − H 4-(4′-CN- 4-CF₃—C₆H₄ 24.90 − biphenyl)** H 4-(4′-CN- 4-CN—C₆H₄29.80 − biphenyl)** H 4-(4′-CN- 4-Cl—C₆H₄ 13.10 − biphenyl)** H4-Cl—C₆H₄** 3,4-diCl—C₆H₄ 58.0 − H 4-Cl—C₆H₄** 2,4-diCl—C₆H₄ 91.40 − H4-F—C₆H₄** 4-OCF₃—C₆H₄ 51.60 − H 4-CN—C₆H₄** 4-OCF₃—C₆H₄ 90.00 + H4-CN—C₆H₄** 4-OCHF₂—C₆H₄ 48.40 − H 4-CN—C₆H₄** 4-OCF₂CHF₂—C₆H₄ 92.80 − H4-CN—C₆H₄** 5-chlorothiophen-2-yl 20.60 − H 4-CN—C₆H₄**2,2difluoro-1,3-dioxol- 88.10 − C₆H₃-5-yl H 4-OCF₃—C₆H₄** 3,5-diCl—C₆H₃33.40 − H 4-OCF₃—C₆H₄** 3,4-diF—C₆H₃ 100.0 + H 4-OCF₃—C₆H₄**4-n-propoxy-C₆H₄ 10.40 − H 4-OCF₃—C₆H₄** 3,4-diCl—C₆H₃ 100.0 + H4-OCF₃—C₆H₄** 3-F-4-CF₃—C₆H₃ 44.20 − H 4-OCF₃—C₆H₄**5-chlorothiophen-2-yl 26.10 − H 4-OCF₃—C₆H₄** thiophen-2-yl 0.00 − H4-OCF₃—C₆H₄** 4-phenoxy-C₆H₄ 0.00 − H 4-OCF₃—C₆H₄** pyridine-3-yl 0.00 −H 4-OCF₃—C₆H₄** 4-OCF₃—C₆H₄ 100.0 + H 4-OCF₃—C₆H₄** 4-F—C₆H₄ 0.00 + H4-OCF₃—C₆H₄** 4-CN—C₆H₄ 88.90 + H 4-OCF₃—C₆H₄** 4-Cl—C₆H₄ 100.0 + H4-OCF₃—C₆H₄** 4-OCHF₂—C₆H₄ 44.20 − H 4-OCF₃—C₆H₄** 2-F-5-CF₃—C₆H₃ 29.50− H 4-OCF₃—C₆H₄** 4-CF₃—C₆H₄ 55.50 + H 4-OCF₃—C₆H₄** 3-F-5-CF₃—C₆H₃42.90 − H 4-OCF₃—C₆H₄** 2-F-4-CF₃—C₆H₃ 100.0 + H 4-OCF₃—C₆H₄**4-OCF₂CHF₂—C₆H₄ 47.10 − H 4-OCF₃—C₆H₄** 2,2difluoro-1,3-dioxol- 27.70 +C₆H₃-5-yl H 4-OCF₃—C₆H₄** pyridine-4-yl 0.00 − H 4-OCF₃—C₆H₄**pyridine-2-yl 0.00 − H 4-OCF₃—C₆H₄** 3-Br-pyridine-2-yl 26.90 − H4-OCF₃—C₆H₄** 4-(4-F-phenyl)-pyridin-3-yl 12.80 − H 4-OCF₃—C₆H₄**4-(thiophen-2-yl)- 12.80 − pyridin-3-yl H 4-OCF₃—C₆H₄**4-(4-OCF₃-phenyl)- 82.60 − pyridin-3-yl H 4-OCF₃—C₆H₄**4-(5-Cl-thiophen-2-yl)- 88.50 − pyridin-3-yl H 4-OCF₃—C₆H₄**4-(4-Cl-phenyl)- 84.60 − pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(3-Cl-phenyl)-66.80 − pyridin-3-yl H 4-OCF₃—C₆H₄** 4-Br-pyridine-3-yl 12.80 − *Eisomer **Mixture of Z and E isomers

1. A compound of formula I

wherein R is H; R₁ is phenyl optionally substituted with one, two orthree halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted, biphenyl optionallysubstituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅,NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted, naphthyl optionally substituted with one, two or threehalogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted, or heteroaryl optionallysubstituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅,NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted; R₂ is phenyl optionally substituted with one, two or threehalogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl or heteroaryl group each optionally substituted with theproviso that only one of R₁ or R₂ may be an optionally substitutedphenyl group; biphenyl optionally substituted with one, two or threehalogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted; naphthyl optionallysubstituted with one, two or three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄,NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted; heteroaryl optionally substituted with one, two or threehalogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, phenyl or heteroaryl group each optionally substituted; orC₃-C₆cycloalkyl optionally substituted with one, two or three halogen,CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkylor a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl groupeach optionally substituted; R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are eachindependently H, C₁-C₆, haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroaryl group eachoptionally substituted; R₅, R₇, R₁₄ and R₁₆ are each independently aC₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl orheteroaryl group each optionally substituted; R₆, R₈, R₁₅ and R₁₇ areeach independently H or an optionally substituted C₁-C₆alkyl group; andR₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆, haloalkyl, or aC₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl orheteroaryl group each optionally substituted or R₁₀ and R₁₁ or R₁₉ andR₂₀ may be taken together with the atom to which they are attached toform an optionally substituted 5- to 7-membered ring optionallycontaining one or two additional heteroatoms selected from N, O or S; orthe stereoisomers thereof, the tautomers thereof or the pharmaceuticallyacceptable salts thereof.
 2. The compound according to claim 1 whereinR₂ is an optionally substituted biphenyl or naphthyl group.
 3. Thecompound according to claim 1 wherein R₁ is phenyl substituted with oneor two halogen or C₁-C₆haloalkyl groups.
 4. The compound according toclaim 1 wherein R₁ is an optionally substituted biphenyl group and R₂ isan optionally substituted phenyl group.
 5. The compound according toclaim 2 wherein R₁ is an optionally substituted phenyl group.
 6. Thecompound according to claim 3 wherein R₂ is naphthyl or a biphenyl groupoptionally substituted with one or two halogen, OR₁₂, COR₁₃,C₁-C₆haloalkyl or C₁-C₆alkyl groups.
 7. The compound according to claim4 wherein R₁ is a biphenyl group substituted with one or two halogen. 8.The compound according to claim 7 wherein R₂ is a phenyl groupsubstituted with one or two halogen or C₁-C₆haloalkyl groups.
 9. Thecompound according to claim 1 selected from the group consisting of:(5Z)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)methylene]-3-(3,5-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;(5Z)-5-[(3′,4′-dichloro-1,1′-biphenyl-2-yl)methylene]-3-(3,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3-chlorophenyl)-4-hydroxy-2(5H)-furanone;(5E)-5-[2′-chloro-2-methyl-1,1′-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl)-4-hydroxyfuran-2(5H)-one;(5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{[2-methoxy-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene}furan-2(5H)-one;(5Z)-3-(3,5-dichlorophenyl)-5-[2,2′-dimethyl-1,1′-biphenyl-4-yl)methylene]-4-hydroxyfuran-2(5H)-one;5-{[2-chloro-3-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4-hydroxyfuran-2(5H)-one;3-(3-fluoro-4-biphenyl)-5-{[2-fluoro-5-(trifluoromethyl)phenyl]methylene}-4-hydroxyfuran-2(5H)-one;(5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{[2-methyl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene}furan-2(5H)-one;(5Z)-5-[3-(benzyloxy)benzylidene]-3-(3,5-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;(5Z)-5-[(2′-acetyl-2-methyl-1,1′-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl)-4-hydroxyfuran-2(5H)-one;5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3,4-dichlorophenyl)-4-hydroxy-2(5H)-furanone;5-[Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3,5-dichlorophenyl)-4-hydroxy-2(5H)-furanone;3-(2-fluoro[1,1′-biphenyl]-4-yl)-4-hydroxy-5-{(Z)-[3-(trifluoromethyl)phenyl]-methylidene}furan-2(5H)-one;5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-2(5H)-furanone;(5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-(1-napthylmethylene)furan-2(5H)-one;5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4-hydroxyfuran-2(5H)-one;5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(4′-ethoxy-4-biphenyl)-4-hydroxyfuran-2(5H)-one;(5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{(4-methoxy-1-naphthyl)methylene]-furan-2(5H)-one;(5Z)-3-(3-chlorophenyl)-4-hydroxy-5-{[2-methyl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene]furan-2(5H)-one;(5Z)-5-[(3′-4′-dichloro-1,1′-biphenyl-3-yl)methylene]-3-(3,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;the stereoisomers thereof; the tautomers thereof; and thepharmaceutically acceptable salts thereof.
 10. A method for the controlof nematode pests or parasites which comprises contacting said pests orparasites, their food supply, habitat or breeding ground with apesticidally or parasiticidally effective amount of a compound offormula I

wherein R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionallysubstituted; R₁ is phenyl optionally substituted with one, two or threehalogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted, biphenyl optionallysubstituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅,NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted, naphthyl optionally substituted with one, two or threehalogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted, or heteroaryl optionallysubstituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅,NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted; R₂ is phenyl optionally substituted with one, two or threehalogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl or heteroaryl group each optionally substituted; biphenyloptionally substituted with one, two or three halogen, CN, OR₁₂, COR₁₃,SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted; naphthyl optionally substituted with one, two or threehalogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted; heteroaryl optionallysubstituted with one, two or three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄,NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl groupeach optionally substituted; or C₃-C₆cycloalkyl optionally substitutedwith one, two or three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally substituted; R₃, R₄,R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆, haloalkyl, or aC₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl orheteroaryl group each optionally substituted; R₅, R₇, R₁₄ and R₁₆ areeach independently a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkyl, benzyl, aryl or heteroaryl group each optionallysubstituted; R₆, R₈, R₁₅ and R₁₇ are each independently H or anoptionally substituted C₁-C₆alkyl group; and R₁₀, R₁₁, R₁₉ and R₂₀ areeach independently H, C₁-C₆, haloalkyl, or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroarylgroup each optionally substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may betaken together with the atom to which they are attached to form anoptionally substituted 5- to 7-membered ring optionally containing oneor two additional heteroatoms selected from N, O or S; or a stereoisomerthereof, a tautomer thereof or a pharmaceutically acceptable saltthereof.
 11. A method for the protection of a growing or harvested plantfrom attack or infestation by nematode pests or parasites whichcomprises applying to the foliage of said plant or to the soil or waterin which it is growing a pesticidally effective amount of a compound offormula I

wherein R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionallysubstituted; R₁ is phenyl optionally substituted with one, two or threehalogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted, biphenyl optionallysubstituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅,NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted, naphthyl optionally substituted with one, two or threehalogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted, or heteroaryl optionallysubstituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅,NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted; R₂ is phenyl optionally substituted with one, two or threehalogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl or heteroaryl group each optionally substituted; biphenyloptionally substituted with one, two or three halogen, CN, OR₁₂, COR₁₃,SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionallysubstituted; naphthyl optionally substituted with one, two or threehalogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀,C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl orC₂-C₆alkynyl group each optionally substituted; heteroaryl optionallysubstituted with one, two or three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄,NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl groupeach optionally substituted; or C₃-C₆cycloalkyl optionally substitutedwith one, two or three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally substituted; R₃, R₄,R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆, haloalkyl, or aC₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl orheteroaryl group each optionally substituted; R₅, R₇, R₁₄ and R₁₆ areeach independently a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,C₂-C₆alkyl, benzyl, aryl or heteroaryl group each optionallysubstituted; R₆, R₈, R₁₅ and R₁₇ are each independently H or anoptionally substituted C₁-C₆alkyl group; and R₁₀, R₁₁, R₁₉ and R₂₀ areeach independently H, C₁-C₆, haloalkyl, or a C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroarylgroup each optionally substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may betaken together with the atom to which they are attached to form anoptionally substituted 5- to 7-membered ring optionally containing oneor two additional heteroatoms selected from N, O or S; or a stereoisomerthereof, a tautomer thereof or a pharmaceutically acceptable saltthereof.